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WO2025226862A1 - Cyclin inhibitors - Google Patents

Cyclin inhibitors

Info

Publication number
WO2025226862A1
WO2025226862A1 PCT/US2025/026047 US2025026047W WO2025226862A1 WO 2025226862 A1 WO2025226862 A1 WO 2025226862A1 US 2025026047 W US2025026047 W US 2025026047W WO 2025226862 A1 WO2025226862 A1 WO 2025226862A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
independently
compound
pharmaceutically acceptable
acceptable salt
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/US2025/026047
Other languages
French (fr)
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 WO2025226862A1 publication Critical patent/WO2025226862A1/en
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
    • 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
    • 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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof

Definitions

  • cyclins including Cyclins D, E, A and B
  • CDKs cognate cyclin dependent kinases
  • CDKs 1 2, 4 and 6 cognate 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 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 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.
  • a compound of Formula (I) PATENT Attorney Docket No.052687-509001WO (I) wherein 3 R is (a) C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, or C1-8 haloalkyl, each substituted with 0, 1, 2, 3, 4, or 5 R 3a , (b) C3-12 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, 4, or 5 R 3c ; (g) heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N
  • 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 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 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 preparation of compounds of Formula (I).
  • CDKs cyclin dependent kinases
  • 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. 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. Nat Cell Biol.1999.1(7):438-43) and contains a highly conserved MRAIL motif.
  • 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, 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 hydrocarbon radical. The two moieties linked to the alkylene can be linked to the same atom PATENT Attorney Docket No.052687-509001WO or different atoms of the alkylene group.
  • a straight chain alkylene can be the bivalent radical of –(CH2)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 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 C 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 , and C6.
  • Alkenyl groups can have any suitable number of double bonds, including, but not 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 C 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C3-6, C3-7, C4, C4-5, C4-6, C4-7, C6-7, C5, C6 and C7.
  • the two moieties linked to the alkenylene can be linked to the same atom or different atoms of the 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, 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 as C 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 , and C6.
  • 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 unsubstituted.
  • PATENT Attorney Docket No.052687-509001WO “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, 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, 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 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 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, 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, 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 C3-6, C4-6, C5-6, C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 , and C 3-12 . 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] bicyclooctane, decahydronaphthalene and adamantane.
  • Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring, but cycloalkyl PATENT Attorney Docket No.052687-509001WO 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, 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, 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 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 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, 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, thiazolidine, isothiazolidine, dioxolane,
  • 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-, 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 PATENT Attorney Docket No.052687-509001WO 2-, 3-, 4- or 5-oxazolidine
  • isoxazolidine can be 2-, 3-, 4- or 5-isoxazolidine
  • 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 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 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 linking group.
  • Some aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl.
  • Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl.
  • 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 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.
  • heteroaryl groups 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 PATENT Attorney Docket No.052687-509001WO 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, isothiazole, oxazole, and isoxazole.
  • PATENT Attorney Docket No.052687-509001WO 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, isothiazole, oxazole, and isoxazole
  • the 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 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 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 5-isothiazole
  • oxazole includes 2-, 4- and 5-
  • 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, 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, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,
  • 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, 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, 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 ring atoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • 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 formulation and/or administration of an active agent to a subject.
  • Pharmaceutical excipients 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 (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 device e.g., a mini-osmotic pump, to the subject.
  • a slow-release device e.g., a mini-osmotic pump
  • Treatment refers to any indicia of success in the treatment or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any 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 3 R is (a) C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, or C1-8 haloalkyl, each substituted with 0, 1, 2, 3, 4, or 5 R 3a , (b) C3-12 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, 4, or 5 R 3c ; (g) heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, where
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) having the structure of Formula (Ia): .
  • R 8f , and ring B can each independently be as defined for any embodiment of Formula (Ia) as described herein.
  • Residue 3 [0042]
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), 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) or (Ia), 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) or (Ia), 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) or (Ia), 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) or (Ia), wherein each R 3a is –OH or C1-6 alkoxy.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein each R 3a is –OH.
  • R 3a can be 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) or (Ia), 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) or (Ia), wherein R 3 is (b) C3-7 cycloalkyl substituted with 0, 1, 2, or 3 R 3b .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein R 3 is (b) C 5-6 cycloalkyl substituted with 0, 1, or 2 R 3b .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein R 3 is (b) C 3-4 cycloalkyl substituted with 0, 1, or 2 R 3b . These embodiments of R 3 can be combined with any of the embodiments described herein for R 3b .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), 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) or (Ia), wherein each R 3b is halo or C 1-4 haloalkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein each R 3b is fluoro or trifluoromethyl. These embodiments of R 3b can be 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) or (Ia), wherein R 3 is (c) heterocycloalkyl having 3 to 6 ring 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) or (Ia), 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 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 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 3c is halo or C1-4 haloalkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein each R 3c is fluoro or trifluoromethyl. These embodiments of R 3c can be combined with any of the embodiments described herein for R 3 .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), 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 pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), 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 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 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 3g is halo or C 1-4 haloalkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), 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 thereof is the compound of Formula (I) or (Ia), wherein R 3 is . [0051] Any of the can be combined with any of the embodiments described herein for residues 4, 5, 6, 7, and 8.
  • any of the embodiments of R 3 as described herein can be combined with any of the embodiments described herein for R 4a , R 4b , R 4c , X 5 , ring C, R 6b , X 6 , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8, and R 8f .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein R 4a , R 4b , and R 4c are each independently H or C 1-6 alkyl; 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.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein R 4a , R 4b , and R 4c are each independently H or C1-6 alkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein R 4b is H or C1-6 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) or (Ia), 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 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) or (Ia), 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 a pyrrolidinyl, substituted with 0, 1, or 2 R 4a1 .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein R 4a1 is C1-6 alkyl or halo.
  • the compound, or the pharmaceutically acceptable salt thereof is the PATENT Attorney Docket No.052687-509001WO compound of Formula (I) or (Ia), wherein R 4a1 is halo.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein R 4a1 is fluoro.
  • R 4a , R 4b and R 4c can be present in any combination.
  • residue 4 can be present in combination with any of the embodiments described herein for residues 3, 5, 6, 7, and 8.
  • 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 , X 5 , ring C, R 6b , X 6 , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8, and R 8f .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein X 5 is a bond.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein X 5 is –C(O)NR 5d –
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein R 5d is H.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein R 5d is C 1-6 alkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein ring C is 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, or 4 R 5e .
  • This embodiment of ring C can be combined with any of the embodiments described herein for X 5 .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein wherein ring C is heteroaryl having 9 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein the heteroaryl is substituted with 0, 1, 2, 3, or 4 R 5e .
  • This embodiment of ring C can be combined with any of the embodiments described herein for X 5 .
  • PATENT Attorney Docket No.052687-509001WO is the compound of Formula (I) or (Ia), wherein ring C is a heteroaryl as defined above and is substituted with 0, 1, 2, or 3 R 5e .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein ring C is a heteroaryl as defined above and is substituted with 0, 1, or 2 R 5e .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein ring C is a heteroaryl as defined above and is substituted with 0 or 1 R 5e .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein ring C is a heteroaryl as defined above and is substituted with 0 R 5e .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein ring C is a heteroaryl as defined above and is substituted with 1 R 5e .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein ring C is a heteroaryl as defined above and is substituted with 2 R 5e .
  • R 5e can be combined with any of the embodiments described herein for ring C and X 5 .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein R 5e is independently C 1-6 alkyl, –OH, halo, or oxo. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R 5e is independently C 1-6 alkyl or oxo. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R 5e is independently halo or oxo. These embodiments of R 5e can be combined with any of the embodiments described herein for ring C and X 5 .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein ring C is .
  • ring C is .
  • Certain ring C moieties can exist as tautomers. All possible tautomers are within the scope of this disclosure.
  • an oxo substituted ring C moiety can exist as a tautomer as shown below: .
  • the embodiments C can be present in any combination.
  • the embodiments described herein for residue 5 can be present in combination with any of the embodiments described herein for residues 3, 4, 6, 7, and 8.
  • any of the embodiments of X 5 and ring C as described herein can be combined with any of the embodiments described herein for R 3 , R 4a , R 4b , R 4c , R 6b , X 6 , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8, and R 8f .
  • Residue 6 [0069]
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein X 6 is C 6-7 alkylene.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein X 6 is C 6-7 alkenylene. These embodiments of X 6 can be combined with any of the embodiments described herein for R 6b and R 6d .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein X 6 is . This embodiment of X 6 can be the embodiments described herein for R 6b and R 6d .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein X 6 is PATENT Attorney Docket No.052687-509001WO , wherein the wavy bond attached to E, Z, or a mixture of both isomers.
  • This embodiment of X 6 can any of the embodiments described herein for R 6b and R 6d .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein R 6b and R 6d are each independently H or C 1-6 alkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein 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) or (Ia), wherein R 6b and R 6d are each H. These embodiments of R 6b and R 6d can be combined with any of the embodiments described herein for X 6 .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein R 6b is H; and R 6d is H, methyl, or ethyl.
  • R 6b and R 6d can be combined with any of the embodiments described herein for X 6 .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein R 6b is H; and R 6d is H or methyl.
  • R 6b and R 6d can be combined with any of the embodiments described herein for X 6 .
  • the embodiments described herein for X 6 , R 6b and R 6d 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 X 6 , R 6b and R 6d as described herein, can be combined with any of the embodiments described herein for R 3 , R 4a , R 4b , R 4c , X 5 , ring C, R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8, and R 8f .
  • 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- 6 alkyl; and R 7c is C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 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 C1- 6 alkyl; and R 7c is C 1-6 alkyl, C 3-6 cycloalkyl, or –C 1-6 alkyl–C 3-6 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 C1- 6 alkyl; and R 7c is C 1-6 alkyl or C 1-6 haloalkyl.
  • 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 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, . 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 , X 5 , ring C, R 6b , X 6 , R 6d , R 8a , R 8b , R 8d , R 8e , ring B, m8, and R 8f .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein R 8a , R 8b , R 8d , and R 8e are each PATENT Attorney Docket No.052687-509001WO independently H or C 1-6 alkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), 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) or (Ia), 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) or (Ia), wherein ring B is phenyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein ring B is biphenyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), 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. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), 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) or (Ia), wherein ring B is pyridyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein ring B is pyrid-3-yl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein ring B is phenyl or pyridyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein ring B is phenyl or pyrid-3-yl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein the subscript m8 is 1, 2, or 3. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein the subscript m8 is 0. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein the subscript m8 is 1.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein the subscript m8 is 2.
  • the compound, or the pharmaceutically acceptable PATENT Attorney Docket No.052687-509001WO salt thereof is the compound of Formula (I) or (Ia), wherein the subscript m8 is 3.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein the subscript m8 is 4.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein the subscript m8 is 5.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein the moiety .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein the moiety .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein the moiety .
  • PATENT Attorney Docket No.052687-509001WO These embodiments can be combined with any of the embodiments described herein for R 8a , R 8b , R 8d , R 8e , R 8f , R 8f3 , m8 and ring B.
  • at least one R 8f is halo.
  • At least one R 8f is fluoro or chloro. These embodiments of 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) or (Ia), wherein each R 8f is independently C 1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C1-6 deuteroalkoxy, halo, C1-6 haloalkyl, cyano, or –X 8f –cyano.
  • 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) or (Ia), wherein each X 8f is independently C1-6 alkylene.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein each X 8f is independently C2-6 alkenylene.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein each X 8f is independently –O–C1-6 alkylene. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each X 8f is independently O. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each X 8f is independently S. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each X 8f is independently C1-6 alkylene or O.
  • 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) or (Ia), wherein each R 8f is independently C 1-4 alkyl, C2-4 alkenyl, C1-4 alkoxy, C1-4 deuteroalkoxy, halo, C1-4 haloalkyl, cyano, or –C1-2 alkyl– PATENT Attorney Docket No.052687-509001WO cyano.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), 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 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 cyclo
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), 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 .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein each R 8f is independently halo, PATENT Attorney Docket No.052687-509001WO heterocycloalkyl, –O–heterocycloalkyl, phenyl, or –O–phenyl, wherein each heterocycloalkyl 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 thereof is the compound of Formula (I) or (Ia), 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 heterocycloalkyl is substituted with 0, 1, 2, or 3 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 thereof is the compound of Formula (I) or (Ia), wherein each R 8f3 is C1-6 alkyl, –Y 8 –C1-6 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–
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein each R 8f3 is independently C 1-6 alkyl, –Y 8 –C1-6 alkyl, C1-6 deuteroalky, –Y 8 –C1-6 deuteroalkyl, –OH, –C1-6 alkyl–OH, –Y 8 –C1-6 alkyl–OH, –C 1-6 alkyl–Y 8 –C 1-6 alkyl, halo, C 1-6 haloalkyl, –Y 8 –C 1-6 haloalkyl, or oxo; each Y 8 is independently C(O), C(O)O, N(R 8f4 )C(O), O, S, or S(O)2; and each R 8f4 is independently H or C 1-6 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, and R 8f .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein each Y 8 is independently –Y 8 –C 1-6 alkyl.
  • the compound, or the pharmaceutically acceptable salt thereof, PATENT Attorney Docket No.052687-509001WO is the compound of Formula (I) or (Ia), wherein each Y 8 is independently –Y 8 –methyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein each Y 8 is independently C(O). In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), 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) or (Ia), wherein each Y 8 is independently NHC(O). In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each Y 8 is independently O.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein each Y 8 is independently S. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), 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) or (Ia), wherein each R 8f3 is independently C1-6 alkyl, C 1-6 deuteroalky, –OH, –C 1-6 alkyl–OH, halo, C 1-6 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 .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein each R 8f3 is independently C1-6 alkyl or –Y 8 –C 1-6 alkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein each Y 8 is independently a C(O) or C(O)O.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein each R 8f3 is independently C 3-6 cycloalkyl, –X 8f3 –C3-6 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 S(O)2; and each X 8f3 is independently C1-6 alkylene, C(O), or S(O)2.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein each X 8f3 is independently C 1-6 alkylene. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each X 8f3 is independently C(O).
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein each X 8f3 is independently S(O) 2 .
  • X 8f3 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) or (Ia), wherein each R 8f3 is independently C3-6 cycloalkyl or heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 members and 1 to 2 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 thereof is the compound of Formula (I) or (Ia), 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 thereof is the compound of Formula (I) or (Ia), wherein each R 8f3 is independently C 1-4 alkyl, C1-4 alkoxy, C2-6 alkoxyalkyl, –S(O)2–C1-4 alkyl, –C1-4 alkyl–S(O)2–C1-4 alkyl, halo, C1-4 haloalkyl, oxo, –C(O)–C 1-4 alkyl, or –C(O)O–C 1-4 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, and R 8f .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein each R 8f3 is independently C1-4 alkyl, C 1-4 alkoxy, C 2-6 alkoxyalkyl, halo, C 1-4 haloalkyl, oxo, –S(O) 2 –C 1-4 alkyl, –C 1-4 alkyl–S(O) 2 – C1-4 alkyl,–C(O)–C1-4 alkyl, –C(O)O–C1-4 alkyl, C3-6 cycloalkyl, –C(O)–C3-6 cycloalkyl, – S(O) 2 –C 3-6 cycloalkyl, heterocycloalkyl, –
  • 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) or (Ia), wherein m8 is 2; and each R 8f is independently fluoro, chloro, bromo, , [0113] thereof, is the compound of Formula (I) or (Ia), wherein m8 is 2; and each R 8f is independently chloro, bromo, , PATENT Attorney Docket No.052687-509001WO [0114]
  • the embodiments described herein for R 8a , R 8b , R 8d , R 8e , m8 and R 8f can be present in any combination.
  • any of the embodiments of R 8a , R 8b , R 8d , R 8e , ring B, 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 , X 5 , ring C, R 6b , X 6 , R 6d , R 7a , R 7b , and R 7c .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia), wherein R 3 is ; 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 or 1 fluoro;
  • X 5 is a bond or –C(O)NH–;
  • ring C is ;
  • X 6 is ;
  • R 6b is R 6d is H or methyl;
  • R 7a is H;
  • R 7b is H;
  • PATENT Attorney Docket No.052687-509001WO R 7c is isobutyl;
  • R 8a is methyl;
  • R 8b , R 8d and R 8e are each H;
  • ring B is phenyl, biphenyl, or pyridyl;
  • m8 is 2; and each R 8f is independently fluoro, chloro, bro
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (Ia) having the structure of any one of Examples 1-36.
  • 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 PATENT Attorney Docket No.052687-509001WO of Formula (I) or (Ia) can have asymmetric centers at one or more carbon atoms, and therefore compounds of Formula (I) or (Ia) can exist in diastereomeric or enantiomeric forms or mixtures thereof.
  • 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, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.
  • salts of the acidic compounds of Formula (I) or (Ia) are salts 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.
  • cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium
  • ammonium salts such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl
  • 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 PATENT Attorney Docket No.052687-509001WO 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 compound for the purposes of the present disclosure.
  • the present disclosure also includes isotopically-labeled compounds of Formula (I) or (Ia), 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) or (Ia) include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, 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) or (Ia) 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) or (Ia) can generally be prepared according to methods known in the art.
  • IV. Compositions [0125] The compounds of Formula (I) or (Ia) described herein are useful in the manufacture of a 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) or (Ia) can be administered to a 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. Martin.
  • Compounds of Formula (I) or (Ia) 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, subcutaneously, intramuscularly, etc.), and combinations thereof.
  • the compounds of Formula (I) or (Ia) is dissolved in a liquid, for example, water.
  • suitable route of administration for a compound of Formula (I) or (Ia) 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) or (Ia) 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) or (Ia) disclosed herein.
  • 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 intravenously. In preferred embodiments, 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 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, 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 carboxymethylcellulose
  • the tablet contains a mixture of hydroxypropyl methylcellulose, polyethyleneglycol 6000 and titatium dioxide. Tablets can be either film coated or enteric coated according to methods known in the art. PATENT Attorney Docket No.052687-509001WO [0130] 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 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 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, 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 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 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 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.
  • PATENT Attorney Docket No.052687-509001WO PATENT Attorney Docket No.052687-509001WO
  • the compounds of Formula (I) or (Ia) 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.
  • compositions of Formula (I) or (Ia) set forth herein can be formulated for parenteral 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, 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 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.
  • HPI3CD 2-hydroxypropyl-13-cyclodextrin
  • the present disclosure contemplates the use of the compounds of Formula (I) or (Ia) 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 disclosure provides a method of treating a cancer mediated at least in part by cyclin activity, PATENT Attorney Docket No.052687-509001WO 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 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 compounds of Formula (I) or (Ia) for use in therapy.
  • the present disclosure contemplates the use of the compounds of Formula (I) or (Ia) 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 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 condition or disorder mediated at least in part by cyclin A comprising administering a compound of Formula (I) or (Ia) described herein.
  • provided herein are compounds of Formula (I) or (Ia) 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) or (Ia) 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 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) or (Ia) described herein.
  • provided herein are compounds of Formula (I) or (Ia) for use in a 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 Formula (I) or (Ia) 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 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 E comprising administering a compound of Formula (I) or (Ia) described herein.
  • provided herein are compounds of Formula (I) or (Ia) for use in a method for treating a proliferative condition or disorder mediated at least in part by cyclin E.
  • compounds of Formula (I) or (Ia) for the manufacture of a medicament for the treatment of a proliferative condition or disorder mediated at least in part by cyclin E.
  • the compounds of Formula (I) or (Ia) described herein can be used to treat or prevent a proliferative condition or disorder, including 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- PATENT Attorney Docket No.052687-509001WO small-cell lung carcinoma, small cell lung cancer), pancreas, salivary gland, adrenal gland, thyroid, brain, ganglia, central nervous system (CNS) and peripheral nervous system (PNS), and cancers of the hematopoietic system and the immune system (e.g., spleen or thymus).
  • a cancer for example, cancer of the uterus, cer
  • 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., 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., epithelial cell cancers, endothelial cell cancers, squamous cell carcinomas and papillomavirus
  • adenocarcinomas e.g., epithelial cell cancers, endothelial cell cancers, squamous cell carcinomas and papillomavirus
  • adenocarcinomas e.g., epithelial cell cancers, endot
  • 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.
  • Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracisternal, intraarticular, intraperitoneal, PATENT Attorney Docket No.052687-509001WO intracerebral (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 intraarticular
  • intraperitoneal PATENT Attorney Docket No.052687-509001WO intracerebral (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 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 (Ia) or pharmaceutical compositions or medicaments thereof can be administered to a subject diagnosed or suspected of having a disease or disorder 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 optimum dosages, dosing methodologies, and repetition rates.
  • a unit dosage for oral administration of a compound of Formula (I) or (Ia) 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).
  • a unit dosage for subcutaneous administration of a compound of Formula (I) or (Ia) 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 administered in multiple doses, e.g., twice, three times, or four times per day. However, as PATENT Attorney Docket No.052687-509001WO 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.
  • the compounds are administered for one or more 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 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. While compounds that exhibit toxic side-effects can be used, care should be taken to design a delivery system that targets such compounds to the affected site to minimize potential damage to normal cells and, thereby, reduce side-effects.
  • compositions or medicaments of the present disclosure can be monitored and adjusted throughout treatment, depending on severity of symptoms, frequency of recurrence, and/or the physiological response to the therapeutic 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.
  • the composition or medicament should provide a sufficient quantity of the compounds of the disclosure to effectively treat the patient. Generally, when treating cancer, the dose is sufficient to stop tumor growth or cause tumor regression without producing unacceptable toxicity or side-effects to the patient. VII.
  • the present disclosure provides intermediates useful in the preparation of compounds of Formula (I).
  • the intermediate is an External Building Block described herein.
  • the intermediate is a compound produced in Method A, Mathod B, or one of Methods 1-4 for any one of the compounds exemplified herein.
  • the intermediate is one of Int.1-30.
  • the intermediate is a combination of one or more covalently linked External Building Blocks. VIII.
  • kits comprising a compound of Formula (I) or (Ia) 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., 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 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 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 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, PATENT Attorney Docket No.052687-509001WO 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 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.
  • IX. Examples [0178] 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 [0179] 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.
  • Table 1 External Building Blocks of the Present Disclosure INT # IUPAC CAS Number, if known Int.1 hex-5-en-1-amine 34825-70-2 Int.2 N-Methylhex-5-en-1-amine 55863-02-0 Int.3 (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3- (2,5-dichlorophenyl)propanoic acid Int.4 (S)-3-(2-bromo-5-chlorophenyl)-2-((tert- butoxycarbonyl)(methyl)amino)propanoic acid Int.5 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- 761446-44-0 dioxaborolan-2-yl)-1H-pyrazole Int.6 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2- 1151802-22-0 dio
  • Step 2 Methyl (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2,5- dichlorophenyl)propanoate: PATENT Attorney Docket No.052687-509001WO [0181] 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 (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 .
  • 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: [0185] (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 ethyl (S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoate was consumed completely. The reaction mixture was concentrated under reduced pressure at 30 °C to remove half of solvent.
  • Step 4 (S)-3-(2-bromo-5-chlorophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid: [0186] To acid (70.00 g, 251.32 mmol, 1 eq) in THF (750 mL) and NaOH (1 N, 750 mL) was added Boc 2 O (109.70 g, 502.64 mmol, 115.47 mL, 2 eq) at 0 °C, the mixture was stirred at 20 °C for 12 h. 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).
  • Step 2 Methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-cyclopropoxypyridin- 3-yl)propanoate: [0189] was added 1,2-dibromoethane (6.80 g, 36.22 mmol, 0.15 eq) in one portion under N 2 . Then chlorotrimethylsilane (2.62 g, 24.15 mmol, 0.1 eq) was added slowly and the mixture was stirred for 30 min at 25 o C.
  • Step 3 Methyl (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(5-chloro-2- cyclopropoxypyridin-3-yl)propanoate: PATENT Attorney Docket No.052687-509001WO [0190] Into a 1000 mL round-bottom flask were added methyl (2S)-2-[(tert- butoxycarbonyl)amino]-3-(5-chloro-2-cyclopropoxypyridin-3-yl)propanoate (25 g, 67.42 mmol, 1 eq) in DMF (400 mL), Ag 2 O (78.11 g, 337.08 mmol, 5 eq) was added at 0 °C under nitrogen atmosphere.
  • Step 4 Int.7: N N O O NaOH Cl [0191] Into - butoxycarbonyl)(methyl)amino]-3-(5-chloro-2-cyclopropoxypyridin-3-yl)propanoate (20 g, 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 reaction was monitored by LCMS, which showed 2-bromo-5-chloropyridin-3- amine was consumed and one of peak with desired mass was detected.
  • the reaction mixture was filtered, and the filter cake was washed with EtOAc (50 mL x 3) and diluted with water (10 mL), extracted with EtOAc (200 mL x 3). The combined organics were washed with brine (50 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue. The residue was dissolved in DCM (80 mL), and 40 g of silica gel was added.
  • Step 2 5-chloro-3-iodo-2-(1-methyl-1H-pyrazol-4-yl)pyridine: [0194] (9 g, 43.14 mmol, 1 eq) in MeCN (300 mL) was added CuI (9.86 g, 51.76 mmol, 1.2 eq), KI (35.80 g, 215.68 mmol, 5 eq) and tert-butyl nitrite (22.24 g, 215.68 mmol, 25.65 mL, 5 eq), the mixture was stirred at 60 °C for 12 h under N2.
  • Step 3 Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazol- 4-yl)pyridine-3-yl)propanoate: [0195] (20.5 g, 64.16 mmol, 1 eq) in DMF (200 mL) was added (R)-(2-((tert-butoxycarbonyl)amino)-3- methoxy-3-oxopropyl)zinc(II) iodide (50.62 g, 128.31 mmol, 2 eq), Pd 2 (dba) 3 (2.94 g, 3.21 mmol, 0.05 eq) and sPhos (2.63 g, 6.42 mmol, 0.1 eq), the mixture was stirred at 20 °C for 12 h under N 2 .
  • the reaction was monitored by LCMS, which showed 5-chloro-3-iodo-2-(1- methyl-1H-pyrazol-4-yl)pyridine was consumed and one of peak with desired mass was detected.
  • the reaction was quenched by addition of saturated ammonium chloride aqueous PATENT Attorney Docket No.052687-509001WO solution (200 mL) and extracted with EtOAc (100 mL x 3). The combined organics were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was dissolved in DCM (50 mL), and 40 g of silica gel was added.
  • Step 4 (S)-2-((tertbutoxycarbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazol-4- yl)pyridine-3-yl)propanoic acid: [0196] (1- methyl-1H-pyrazol-4-yl)pyridine-3-yl)propanoate (8 g, 20.26 mmol, 1 eq) in THF (100 mL) was added a solution of LiOH.H2O (1.02 g, 24.31 mmol, 1.2 eq) in H2O (50 mL), the mixture was stirred at 20 °C for 1 h.
  • Step 5 Int.15: PATENT Attorney Docket No.052687-509001WO N N N N N N N Cl 1H- pyrazol-4-yl)pyridine-3-yl)propanoic acid (3.7 g, 9.72 mmol, 1 eq) in THF (100 mL) was added NaH (1.94 g, 48.58 mmol, 60% purity, 5 eq) at 0 °C, the mixture was stirred at 0 °C for 1 h under N2. MeI (13.79 g, 97.16 mmol, 6.05 mL, 10 eq) was added to the reaction mixture, the mixture was stirred at 20 °C for 12 h under N 2 .
  • Step 2 Methyl (2S,4R)-1-[3,3-difluoro-1-(trifluoromethyl)cyclobutanecarbonyl]-4- fluoropyrrolidine-2-carboxylate: [0199] To a (110 g, 103.3 mmol, 1 eq, 80%), 3,3-difluoro-1-(trifluoromethyl)cyclobutane-1-carboxylic acid (122.06 g, 103.3 mmol, 1 eq) and TCFH (251.69 g, 154.95 mmol, 1.5 eq) in ACN (1100 mL) was added NMI (245.51 g, 516.49 mmol, 5 eq) dropwise in 45 min at 0 °C.
  • 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 layers were washed with saturated NaHCO 3 (1000 mL x1).
  • the aqueous layer was extracted with EtOAc (300mL x1) again.
  • the combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4 .
  • Step 3 Int.22: PATENT Attorney Docket No.052687-509001WO F F F F 3 [0200] To a (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.
  • Step 3 (2S,4R)-4-fluoro-1-((R)-2-(trifluoromethyl)tetrahydro-2H-pyran-2- carbonyl)pyrrolidine-2-carboxylic acid: [0204] To a 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 the mixture was stirred at 25 °C for 1 hr.
  • Step 3 5-chloro-2-(cyclopropylthio)pyridin-3-amine: PATENT Attorney Docket No.052687-509001WO [0207] To a solution of 5-chloro-2-(cyclopropylthio)-3-nitropyridine (21 g, 91.04 mmol, 1 eq) in EtOH (150 mL) and H2O (150 mL) was added Fe (10.17 g, 182.08 mmol, 2 eq) and NH 4 Cl (9.74 g, 182.08 mmol, 2 eq).
  • Step 4 5-chloro-2-(cyclopropylthio)-3-iodopyridine: [0208] To a g, 49.83 mmol, 1 eq) in HCl (3 M, 83.05 mL, 5 eq) and MeCN (100 mL) was added a solution of NaNO2 (3.78 g, 54.81 mmol, 1.1 eq) in H2O (50 mL) slowly at 0 °C.
  • Step 5 methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2- (cyclopropylthio)pyridin-3-yl)propanoate: PATENT Attorney Docket No.052687-509001WO [0209] A degassed and purged with N2. Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (16 g, 48.61 mmol, 1 eq) in DMF (40 mL) was added dropwise, I 2 (3.70 g, 14.58 mmol, 2.94 mL, 0.3 eq) in DMF (20 mL) was then added dropwise.
  • Step 6 (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-(cyclopropylthio)pyridin-3- yl)propanoic acid: PATENT Attorney Docket No.052687-509001WO [0211] To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2- (cyclopropylthio)pyridin-3-yl)propanoate (0.8 g, 2.07 mmol, 1 eq) in THF (20 mL) and H2O (20 mL) was added LiOH•H 2 O (173.54 mg, 4.14 mmol, 2 eq) and the reaction mixture was stirred at 20 °C for 0.5 hr.
  • Step 7 Int.4: O O H O N O N Cl [0212] (cyclopropylthio)pyridin-3-yl)propanoic acid (1.44 g, 3.86 mmol, 1 eq) in THF (30 mL) was added 60% NaH (463.39 mg, 11.59 mmol, 3 eq) at 0 °C under N 2 . The mixture was stirred at ambient temperature for 0.5 hr. Then, MeI (5.48 g, 38.62 mmol, 2.40 mL, 10 eq) was added and the reaction mixture was stirred at 25 °C for 12 hrs.
  • Step 2 Methyl (S)-2-(4-((tert-butoxycarbonyl)amino)-3-nitro-2-oxopyridin-1(2H)- yl)pent-4-enoate: [0216] To (5 g, 19.590 mmol, 1 equiv) in DMF (80 mL) was added 60% NaH (1175.31 mg, 29.385 mmol, 1.5 equiv) in portions at 0°C. The resulting mixture was stirred for 10 min at 0°C.
  • Step 3 Methyl (S)-2-(3-amino-4-((tert-butoxycarbonyl)amino)-2-oxopyridin-1(2H)- yl)pent-4-enoate: PATENT Attorney Docket No.052687-509001WO [0217] To a stirred mixture of methyl (2S)-2- ⁇ 4-[(tert-butoxycarbonyl)amino]-3-nitro-2- oxopyridin-1-yl ⁇ pent-4-enoate (5 g, 13.611 mmol, 1 equiv) and Zn powder (13.35 g, 204.165 mmol, 15 equiv) in EtOH (500 mL) was added NH 4 Cl (10.92 g, 204.165 mmol, 15 equiv) in H2O (50 mL).
  • Step 4 Methyl (S)-2-(4-((tert-butoxycarbonyl)amino)-3-((2S,4R)-1-(3,3-difluoro-1- (trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxamido)-2- oxopyridin-1(2H)-yl)pent-4-enoate: - -2- oxopyridin-1-yl ⁇ pent-4-enoate (3.27 g, 9.692 mmol, 1 equiv), (2S,4R)-1-[3,3-difluoro-1- (trifluoromethyl)cyclobutanecarbonyl]-4-fluoropyrrolidine-2-carboxylic acid (3.09 g, 9.692 mmol, 1 equiv) and TCFH ( 4.07g, 14.538mmol, 1.5eq) in MeCN (80 mL) was added
  • Step 2 methyl (S)-2-(3-((tert-butoxycarbonyl)amino)-5-methyl-2-oxopyridin-1(2H)- yl)pent-4-enoate: PATENT Attorney Docket No.052687-509001WO [0222] Step of Int.26 step 2.
  • Step 3 Int.27: [0223] 2- oxopyridin-1(2H)-yl)pent-4-enoate (5 g, 14.86 mmol, 1 eq) in EtOAc (75 mL) was added MgI2 (8.27 g, 29.73 mmol, 1.87 mL, 2 eq) . The mixture was stirred at 40 °C for 2h. Upon consumption of starting material (LCMS), the reaction mixture was diluted with H 2 O (2 x 60 mL). Then, 1N HCl (10 mL) was used to adjust the pH to 2 ⁇ 3. The acidified water layer was extracted with EtOAc (3 x 50 mL).
  • Step 3 Int.28: [0226] To methyl 1- yl ⁇ pent-4-enoate (1.8 g, 5.351 mmol, 1 equiv) in THF (10 mL) was added LiOH (0.38 g, 16.053 mmol, 3 equiv) in H2O (10 mL). The resulting mixture was stirred for 1hr at ambient temperature. Upon consumption of starting material (LCMS), the reaction mixture was acidified to ⁇ pH 3 with 1N HCl and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product.
  • LCMS starting material
  • Step 2 methyl (S)-2-(3-((tert-butoxycarbonyl)amino)-5-chloro-2-oxopyridin-1(2H)- yl)pent-4-enoate [0228] To a (2 g, 8.174 mmol, 1.00 equiv) in THF (80 mL) was added 60% NaH (0.43 g, 10.626 mmol, 1.3 equiv) at 0°C. The resulting mixture was stirred for 1hr at room temperature under N 2 .
  • Step 3 Int.29: [0229] To a stirred solution of methyl (2S)-2- ⁇ 3-[(tert-butoxycarbonyl)amino]-5-chloro-2- oxopyridin-1-yl ⁇ pent-4-enoate (0.8 g, 2.242 mmol, 1 equiv) in THF (10 mL) was added LiOH (0.27 g, 11.210 mmol, 5 equiv) in H 2 O (10 mL) at room temperature. The PATENT Attorney Docket No.052687-509001WO resulting mixture was stirred for 30 min. Upon consumption of starting material (monitored by LCMS), the mixture was acidified to pH ⁇ 4 with 1N HCl.
  • Step 1 (R)-2-hydroxypent-4- [0230] A 1 eq) in AcOH (460 mL) and H 2 O (1840 mL) was connected to pump A, a solution of NaNO 2 (170.80 g, 2.48 mol, 2.5 eq) in H2O (460 mL) was connected to pump B. The two pumps were adjusted to a flowrate of 6.5 mL/min to a FEP coil. The reaction was conducted at 40°C for 5 min.
  • Step 4 methyl (S)-2-(3-((tert-butoxycarbonyl) amino)-2-oxopyridin-1(2H)-yl) pent-4- enoate: PATENT Attorney Docket No.052687-509001WO [0233] To a eq) in dioxane (300 mL) was added (Boc) 2 O (97.12 g, 444.99 mmol, 102.23 mL, 2 eq), the mixture was stirred at 110°C. The mixture was concentrated, and the residue was purified by FCC (SiO2, 0-30% EtOAc in pet. ether.
  • Step 5 Int.30: [0235] To a - - oxopyridin-1(2H)- yl)pent-4-enoate (3.3 g, 10.24 mmol, 1 eq) in EtOAc (70 mL) was added MgI2 (5.69 g, 20.47 mmol, 1.29 mL, 2 eq) and stirred at 40°C for 2 h. Upon consumption of starting material (LCMS), the reaction was quenched by the addition of water (200 mL) and extracted with PATENT Attorney Docket No.052687-509001WO EtOAc (80 mL x 3). The aqueous phase acidified by 1M HCl at 0 °C.
  • Steps 1-7 (3S,6S,9S)-3-(2,5-dichlorobenzyl)-9-(2-((2S,4R)-1-(3,3-difluoro-1- (trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidin-2-yl)-4-oxo-3,4- dihydro-5H-imidazo[4,5-c]pyridin-5-yl)-6-isobutyl-1,4-dimethyl-1,4,7- triazacyclohexadecane-2,5,8-trione (Example 3): [0244] Steps 1-7 outlined in Steps 1-7 of Method A.
  • Step 1 (2S,4R)-N-(1-((3S,6S,9S)-3-((5-chloro-2-cyclopropoxypyridin-3-yl)methyl)-6- isobutyl-1,4-dimethyl-2,5,8-trioxo-1,4,7-triazacyclohexadecan-9-yl)-2-oxo-1,2- PATENT Attorney Docket No.052687-509001WO dihydropyridin-3-yl)-1-(3,3-difluoro-1-(trifluoromethyl)cyclobutane-1-carbonyl)-4- fluoropyrrolidine-2-carboxamide (Example 6): to sit for 1 hour.
  • Step 1 Tert-butyl (1-((3S,6S,9S)-3-(2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-5- chlorobenzyl)-6-isobutyl-1,4-dimethyl-2,5,8-trioxo-1,4,7-triazacyclohexadecan-9-yl)-2- oxo-1,2-dihydropyridin-3-yl)carbamate (510): mg, 4 Eq, 0.31 mmol), and Int.11(39 mg, 2.0 Eq, 0.16 mmol) was weighed into a vial and dissolved in 4:11,4-Dioxane:Water (2 mL).
  • Steps 2-3 (2S,4R)-N-(1-((3S,6S,9S)-3-(2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-5- chlorobenzyl)-6-isobutyl-1,4-dimethyl-2,5,8-trioxo-1,4,7-triazacyclohexadecan-9-yl)-2- oxo-1,2-dihydropyridin-3-yl)-1-(3,3-difluoro-1-(trifluoromethyl)cyclobutane-1- carbonyl)-4-fluoropyrrolidine-2-carboxamide (Example 20): PATENT Attorney Docket No.052687-509001WO until the deprotection was complete (monitored by LCMS).
  • Step 3 (2S,4R)-N-(1-((3S,6S,9S)-3-((4-chloro-4'-((2R,6R)-2,6-dimethylmorpholino)- [1,1'-biphenyl]-2-yl)methyl)-6-isobutyl-1,4-dimethyl-2,5,8-trioxo-1,4,7- triazacyclohexadecan-9-yl)-2-oxo-1,2-dihydropyridin-3-yl)-1-(3,3-difluoro-1- (trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxamide (Example 1): mg, 2.0 Eq, 414 ⁇ mol) and PdCl2(dppf)•CH2Cl2 (16.9 mg, 0.1 Eq, 20.7 ⁇ mol) were dissolved in 4:1 Dioxane/Water (4 mL).
  • Example 1 (14.6 mg, 13.6 ⁇ mol, 6.5 %) as a white solid after lyophilization.
  • Step 1 (3S,6S,9S)-3-(5-chloro-2-(6-morpholinopyridin-3-yl)benzyl)-9-(2-((2S,4R)-1-(3,3- difluoro-1-(trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidin-2-yl)-4-oxo-3,4- dihydro-5H-imidazo[4,5-c]pyridin-5-yl)-6-isobutyl-1,4-dimethyl-1,4,7- triazacyclohexadecane-2,5,8-trione (Example 30): PATENT Attorney Docket No.052687-509001WO [0257] Step 1 of Method 4 was performed identically to Step 1 of Method 2 using 514 and Int.19 as starting materials.
  • Example 30 was isolated as a white solid.
  • Table 2 provides information on the methods used to prepare the exemplified compounds in the current application. This table includes a column listing the 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 Example Number Macrocycle Synthesis Final Synthesis 1 Method A with Int.2, Int.4, Method 3 Int.30 2 Method A with Int.2, Int.4, Method 2 with Int.20, int.23 Int.30 3 N/A Method B with Int.1, Int.3, Int.25 4 Method A with Int.2, Int.4, Method 2 with Int.5, Int.22 Int.30 5 Method A with Int.2, Int.4, Method 2 with Int.6, Int.22 Int.30 6 Method A with Int.2, Int.7, Method 1 Int.30 7 Method A with Int.2, Int.7, Method 1 with Int.23 Int.30 8 Method A with Int.2, Int.7, Method 1 with Int..24 Int.30 9 Method A with Int.2, Int.4, Method 2 with Int.6, Int.22 Int.30 10 Method A with Int.2, Int.13, Method 2 with Int
  • Table 4 provides the full chemical structure for each exemplified compound in Table 2.
  • Table 4 Chemical Structure for Exemplary Compounds Described in Table 2 Ex. Chemical Structure Ex. Chemical Structure No. No.
  • Binding affinity for the compounds of Formula (I) were determined by Fluorescence Polarization (FP) competitive assay based on previously established protocols (Andrews et. al., Org Biomol Chem., 2004.2(19):2735-41.; Premnath et. al., J Med Chem., 2015.58(1):433-42.) with modifications as described below. 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. 14-475).
  • 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. After experimental plates are set, they were equilibrated by gentle mixing by placing them on an orbital shaker at 100 rpm for 2 hours at rt and then read on a SpectraMax i3X Multi-Mode Microplate Detection platform.
  • Affinity of the Cyclin/Cdk complexed for the fluorescent labeled probe was determined by adding increasing concentration of each protein complex in buffer containing a carboxyfluorescein labeled probe (FAM probe) at 2 nM (preparation of FAM probe is described below).
  • the half maximal concentration of protein needed for the maximal FP signal were 2 nM for Cyclin A2/Cdk2, 9 nM for Cyclin B1/Cdk1 and 3 nM for Cyclin E1/Cdk2. Methods to prepare the FAM probe are described in the heading below.
  • 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 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 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.
  • 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 washed with 1.0 mL DMF three times. To remove Fmoc, 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.
  • 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 washed with 1.0 mL DMF three times.
  • Fmoc-L-Lysine(Mtt)-OH (KMtt), CAS#167393-62-6, (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 then the resin was washed with 1.0 mL of DMF three times. To 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 PATENT Attorney Docket No.052687-509001WO 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 remove Fmoc, 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 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 remove Fmoc, A mixture of piperidine:DMF (20:80, 1 mL) was added to the resin and agitated for 15 min at rt.
  • PATENT Attorney Docket No.052687-509001WO [0277] 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 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- deprotection steps.
  • the cyclic peptide was then purified via reverse phase HPLC using an Acetonitrile/Water gradient with 0.05% formic acid.
  • MTT Proliferation Assay was used to determine the 50% growth inhibition (GI 50 ) 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 days (NCI-H1048 and OVCAR3)).
  • Roscovitine and staurosporine were used as plate controls.
  • MTT reagent TACS MTT Cell PATENT Attorney Docket No.052687-509001WO Proliferation Assay R&D Systems Catalog #4890-025-K

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Abstract

Disclosed herein are compounds of Formula (I), intermediates thereof, and methods for making the same: (I) Also described herein are the use of such compounds and compositions for the treatment of diseases and disorders that are mediated, at least in part, by one or more cyclins, including cancer.

Description

PATENT Attorney Docket No.052687-509001WO CYCLIN INHIBITORS CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No.63/638,000, filed April 24, 2024, which is incorporated herein in its entirety for all purposes. BACKGROUND [0002] Cyclins are a family of proteins that play a central role in the regulation of the cell cycle. Specific cyclins, including Cyclins D, E, A and B, are expressed at the different stages of the cell cycle, during which they bind and activate their cognate cyclin dependent kinases (CDKs), including CDKs 1, 2, 4 and 6, to form cyclin-CDK complexes that orchestrate progression and transitions through the different stages of the cell cycle. 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. To date, most inhibitors of cyclin-CDK complexes target the kinase activity of CDKs (“CDK inhibitors”) and include therapeutics both in development and approved for clinical use. 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. [0003] Although CDK inhibitors have been developed and proven successful in certain 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 addresses this need by providing compounds that inhibit the binding of substrates to various cyclins, thereby disrupting the function of cyclin-CDK complexes. BRIEF SUMMARY [0004] In one embodiment, provided herein is a compound of Formula (I): PATENT Attorney Docket No.052687-509001WO (I) wherein 3 R is (a) C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, or C1-8 haloalkyl, each substituted with 0, 1, 2, 3, 4, or 5 R3a, (b) C3-12 cycloalkyl substituted with 0, 1, 2, 3, 4, or 5 R3b, 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, 4, or 5 R3c; (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 R3g; each R3a is independently –OH, C1-6 alkoxy, C1-6 haloalkoxy, –O–(CH2CH2O)1-4–C1-4 alkyl, –O–(CH2CH2O)1-4–heterocycloalkyl, C1-3 haloalkoxy, –NR3a1R3a2, –O–C(O)C1-6 alkyl, C3-6 cycloalkyl, phenyl, or heteroaryl, wherein each heterocycloalkyl has 4 to 6 ring members and 1 to 3 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; each R3b is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo, C1-6 haloalkyl, cyano, –OH, C1-6 alkoxy, C1-6 haloalkoxy, –NR3b1R3b2, –N(R3b3)C(O)R3b4, phenyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; each R3c is independently C1-6 alkyl, halo, C1-6 haloalkyl, cyano, oxo, or C3-6 cycloalkyl; each R3g is independently C1-6 alkyl, halo, C1-6 haloalkyl, or C3-6 cycloalkyl; each R3a1, R3a2, R3b1, R3b2, and R3b3 is independently H or C1-6 alkyl; each R3b4 is C1-6 alkyl or C1-6 haloalkyl; R4a is H or C1-6 alkyl; R4b and R4c are each independently H, C1-6 alkyl, –C1-6 alkyl–OH, C1-6 haloalkyl, –NR4c1R4c2, –C1-6 alkyl–NR4c1R4c2, C3-6 cycloalkyl, –C1-6 alkyl–C3-6 cycloalkyl, heterocycloalkyl, PATENT Attorney Docket No.052687-509001WO –C1-6 alkyl–heterocycloalkyl, phenyl, –C1-6 alkyl–phenyl, heteroaryl, or –C1-6 alkyl–heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members and 1 to 3 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; alternatively, R4c and R4a together with the carbon and nitrogen to which each is attached combine to form a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, 3, or 4 R4a1; each R4c1 and R4c2 are independently C1-6 alkyl or C2-6 alkoxyalkyl; each R4a1 is independently C1-6 alkyl, –OH, –C1-6 alkyl–OH, C1-6 alkoxy, halo, or –N(R4a2)S(O)2–C1-4 alkyl; R4a2 is H or C1-6 alkyl; alternatively, two R4a1 groups on adjacent ring atoms combine to form a phenyl ring substituted with 0, 1, or 2 R4a3; each R4a3 is independently C1-6 alkyl, –OH, –C1-6 alkyl–OH, C1-6 alkoxy, or halo; X5 is a bond or –C(O)NR5d–; R5d is H or C1-6 alkyl; ring C is a heteroaryl having 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein the heteroaryl is substituted with 0, 1, 2, 3, or 4 R5e; each R5e is independently C1-6 alkyl, –OH, halo, C1-6 haloalkyl, or oxo; X6 is C6-7 alkylene or C6-7 alkenylene; R6b is H or C1-6 alkyl; R6d is H, C1-6 alkyl, C1-6 deuteroalkyl, –OH, or C2-6 alkoxyalkyl; R7a is H or C1-6 alkyl; R7b and R7c are each independently H, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 alkyl–OH, C3-6 cycloalkyl, or –C1-6 alkyl–C3-6 cycloalkyl; R8a is H, C1-6 alkyl, C1-6 deuteroalkyl, C2-6 alkoxyalkyl, C3-6 cycloalkyl, or –C1-6 alkyl–C3-6 cycloalkyl; R8b, R8d, and R8e are each independently H or C1-6 alkyl; alternatively R8b and R8d together with the carbon to which each is attached combine to form a C3-6 cycloalkyl; ring B is C6-12 aryl or heteroaryl having 5 to 12 ring members and 1 to 6 heteroatoms, each independently N, O, or S; PATENT Attorney Docket No.052687-509001WO the subscript m8 is 0, 1, 2, 3, 4, or 5; each R8f is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 deuteroalkoxy, C2-6 alkoxyalkyl, halo, C1-6 haloalkyl, C1-6 haloalkoxy, cyano, –X8f–cyano, –NR8f1R8f2, –C(O)NR8f1R8f2, –N(R8f1)C(O)R8f2, C3-12 cycloalkyl, –X8f–C3-6 cycloalkyl, heterocycloalkyl, –X8f–heterocycloalkyl, C6-12 aryl, –X8f–C 6-12 aryl, heteroaryl, or –X8f–heteroaryl, wherein each heterocycloalkyl has 3 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein each alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R8f3; alternatively, two R8f groups on adjacent ring vertices combine to form a C3-6 cycloalkyl or a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the cycloalkyl or heterocycloalkyl is substituted with 0, 1, 2, or 3 R8f3; each X8f is independently C1-6 alkylene, C2-6 alkenylene, –O–C1-6 alkylene, C(O), O, or S; each R8f1 and R8f2 are independently H or C1-6 alkyl; each R8f3 is independently C1-6 alkyl, –Y8–C1-6 alkyl, C1-6 deuteroalkyl, –Y8–C1-6 deuteroalkyl, –OH, –C1-6 alkyl–OH, –Y8–C1-6 alkyl–OH, –C1-6 alkyl–Y8–C1-6 alkyl, –(C1-2 alkyl–O)1-4–C1-2 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl, –Y8–C1-6 haloalkyl, cyano, –C1-6 alkyl–cyano, –C1-6 alkyl–NR8gR8h, oxo, C3-6 cycloalkyl, –X8f3–C3-6 cycloalkyl, heterocycloalkyl, –X8f3– heterocycloalkyl, phenyl, –X8f3–phenyl, heteroaryl, or –X8f3–heteroaryl, wherein each heterocycloalkyl has 3 to 12 members and 1 to 4 heteroatoms, each independently N, O, S, or S(O)2, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, and wherein each heterocycloalkyl and heteroaryl are substituted with 0, 1, or 2 C1-4 alkyl or halo; alternatively, two R8f3 groups on the same or adjacent ring vertices combine to form a C3-6 cycloalkyl or a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein nitrogen atom ring members in the heterocycloalkyl are substituted with 0 or 1 C1-4 alkyl; each X8f3 is independently C1-6 alkylene, O, C(O), or S(O)2; each Y8 is independently C(O), C(O)O, N(R8f4)C(O), O, S, or S(O)2; each R8g and R8h is independently H, C1-6 alkyl, or C1-6 haloalkyl; and PATENT Attorney Docket No.052687-509001WO each R8f4 is independently H or C1-6 alkyl; or a pharmaceutically acceptable salt thereof. [0005] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, and a pharmaceutically acceptable excipient. [0006] In another embodiment, the present disclosure provides a method of treating a 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. [0007] In another embodiment, the present disclosure provides a method of treating a 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. [0008] In another embodiment, the present invention provides intermediates useful in the preparation of compounds of Formula (I). [0009] Other objects, features, and advantages of the present disclosure will be apparent to one of skill in the art from the following detailed description and figures. BRIEF DESCRIPTION OF THE DRAWINGS [0010] NOT APPLICABLE DETAILED DESCRIPTION I. General [0011] Provided herein are compounds and compositions that disrupt the typical cellular function of cyclins. Also provided herein are, for example, methods of treating or preventing a disease, disorder or condition, or a symptom thereof, mediated by cyclin activity. [0012] Complexes between cyclins and cyclin dependent kinases (CDKs) are responsible for phosphorylating a wide range of substrates, thereby modulating the activity of the PATENT Attorney Docket No.052687-509001WO substrates. Many of these substrates are important in the cell cycle and the 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. Without being bound to any particular theory, 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. 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. Nat Cell Biol.1999.1(7):438-43) and contains a highly conserved MRAIL motif. Compounds that disrupt the binding of substrates to cyclins have been posited to be of potential therapeutic utility, including in the disruption of cancer cell proliferation (Chen et al. Proc Natl Acad Sci U S A.1999.96(8):4325-9). [0013] Without being bound to any particular theory, it is believed that compounds of the present disclosure inhibit the binding of substrates to the hydrophobic patch region of cyclins including, but not limited to, Cyclins A, E and B. Compounds of the present disclosure include compounds that bind more potently to one or more cyclins. II. Definitions [0014] As used herein, 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 specified value. [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, C1-3, C1-4, C1-5, C1-6, C1-7, C1-8, C1-9, C1-10, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. For example, C1-6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, 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. [0016] “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 hydrocarbon radical. The two moieties linked to the alkylene can be linked to the same atom PATENT Attorney Docket No.052687-509001WO or different atoms of the alkylene group. For instance, a straight chain alkylene can be the bivalent radical of –(CH2)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 unsubstituted. [0017] “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 C6. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of 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. [0018] “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, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C3-6, C3-7, C4, C4-5, C4-6, C4-7, C6-7, C5, C6 and C7. The two moieties linked to the alkenylene can be linked to the same atom or different atoms of the 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, and (Z)-hept-3-enylene. Alkenylene moieties can be in the E or Z isomer. Alkenylene groups can be substituted or unsubstituted. [0019] “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 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 C6. Examples of 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 unsubstituted. PATENT Attorney Docket No.052687-509001WO [0020] “Alkoxy” refers to an alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-. As for alkyl group, alkoxy groups can have any suitable number of carbon atoms, such as C1-6. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. The alkoxy groups can be substituted or unsubstituted. [0021] “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, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, etc. The alkoxy groups can be substituted or unsubstituted. [0022] “Halo” or “halogen” refers to fluorine, chlorine, bromine and iodine. [0023] “Haloalkyl” refers to alkyl, as defined above, where some or all of the hydrogen atoms are replaced with halogen atoms. As for alkyl group, haloalkyl groups can have any suitable number of carbon atoms, such as C1-6. For example, haloalkyl includes trifluoromethyl, flouromethyl, etc. In some instances, the term “perfluoro” can be used to define a compound or radical where all the hydrogens are replaced with fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl. [0024] “Haloalkoxy” refers to an alkoxy group where some or all of the hydrogen atoms are substituted with halogen atoms. As for an alkyl group, haloalkoxy groups can have any suitable number of carbon atoms, such as C1-6. The alkoxy groups can be substituted with 1, 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. [0025] “Cycloalkyl” refers to a saturated or partially unsaturated, monocyclic, spirocyclic, 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 C3-6, C4-6, C5-6, 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] bicyclooctane, decahydronaphthalene and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring, but cycloalkyl PATENT Attorney Docket No.052687-509001WO 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, cyclooctadieneyl (1,3-, 1,4- and 1,5-isomers), norborneneyl, and norbornadieneyl. When cycloalkyl is a C3-6 monocyclic cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexeneyl, cyclohexadieneyl (1,3- and 1,4-isomers). When cycloalkyl is a C5-10 fused bicyclic cycloalkyl, exemplary groups include, but are not limited to bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[4.2.0]octanyl, and octahydro-1H-indenyl. When cycloalkyl is a C5-10 bridged polycyclic cycloalkyl, exemplary groups include, but are not limited to bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, and bicyclo[2.1.1]hexane. When cycloalkyl is a C5-10 spirocycloalkyl, 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 substituted or unsubstituted. [0026] “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 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. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. The heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, 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, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl groups can be unsubstituted or substituted. [0027] The heterocycloalkyl groups can be linked via any position on the ring. For example, 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-, 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 PATENT Attorney Docket No.052687-509001WO 2-, 3-, 4- or 5-oxazolidine, isoxazolidine can be 2-, 3-, 4- or 5-isoxazolidine, thiazolidine can be 2-, 3-, 4- or 5-thiazolidine, isothiazolidine can be 2-, 3-, 4- or 5- isothiazolidine, and morpholine can be 2-, 3- or 4-morpholine. [0028] When 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 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. [0029] “Aryl” refers to an aromatic ring system having any suitable number of ring atoms 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 linking group. Some aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. Aryl groups can be substituted or unsubstituted. [0030] “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 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 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 PATENT Attorney Docket No.052687-509001WO 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, isothiazole, oxazole, and isoxazole. The 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 heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted. [0031] The heteroaryl groups can be linked via any position on the ring. For example, 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 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 5-isothiazole, oxazole includes 2-, 4- and 5- oxazole, isoxazole includes 3-, 4- and 5-isoxazole, indole includes 1-, 2- and 3-indole, isoindole includes 1- and 2-isoindole, quinoline includes 2-, 3- and 4-quinoline, isoquinoline includes 1-, 3- and 4-isoquinoline, quinazoline includes 2- and 4-quinoazoline, cinnoline includes 3- and 4-cinnoline, benzothiophene includes 2- and 3-benzothiophene, and benzofuran includes 2- and 3-benzofuran. [0032] Some 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, 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. Other 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, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Some other 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. PATENT Attorney Docket No.052687-509001WO Still other heteroaryl groups include those having from 5 to 6 ring members and from 1 to 2 ring atoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. [0033] As used herein, the term “oxo” refers to an oxygen atom connected to the point of attachment by a double bond (=O). [0034] “Pharmaceutically acceptable excipient” refers to a substance that aids the formulation and/or administration of an active agent to a subject. Pharmaceutical excipients useful in the present disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure. [0035] “Subject” refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In some embodiments, the subject is a human. [0036] “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 device e.g., a mini-osmotic pump, to the subject. [0037] “Therapeutically effective amount” refers to a dose that produces therapeutic effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins) [0038] “Treat”, “treating” and “treatment” refers to any indicia of success in the treatment or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any 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 treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, e.g., the result of a physical examination. PATENT Attorney Docket No.052687-509001WO III. Compounds [0039] In some embodiments, the present disclosure provides a compound of Formula (I): (I) wherein 3 R is (a) C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, or C1-8 haloalkyl, each substituted with 0, 1, 2, 3, 4, or 5 R3a, (b) C3-12 cycloalkyl substituted with 0, 1, 2, 3, 4, or 5 R3b, 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, 4, or 5 R3c; (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 R3g; each R3a is independently –OH, C1-6 alkoxy, C1-6 haloalkoxy, –O–(CH2CH2O)1-4–C1-4 alkyl, –O–(CH2CH2O)1-4–heterocycloalkyl, C1-3 haloalkoxy, –NR3a1R3a2, –O–C(O)C1-6 alkyl, C3-6 cycloalkyl, phenyl, or heteroaryl, wherein each heterocycloalkyl has 4 to 6 ring members and 1 to 3 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; each R3b is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo, C1-6 haloalkyl, cyano, –OH, C1-6 alkoxy, C1-6 haloalkoxy, –NR3b1R3b2, –N(R3b3)C(O)R3b4, phenyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; each R3c is independently C1-6 alkyl, halo, C1-6 haloalkyl, cyano, oxo, or C3-6 cycloalkyl; each R3g is independently C1-6 alkyl, halo, C1-6 haloalkyl, or C3-6 cycloalkyl; each R3a1, R3a2, R3b1, R3b2, and R3b3 is independently H or C1-6 alkyl; each R3b4 is C1-6 alkyl or C1-6 haloalkyl; PATENT Attorney Docket No.052687-509001WO R4a is H or C1-6 alkyl; R4b and R4c are each independently H, C1-6 alkyl, –C1-6 alkyl–OH, C1-6 haloalkyl, –NR4c1R4c2, –C1-6 alkyl–NR4c1R4c2, C3-6 cycloalkyl, –C1-6 alkyl–C3-6 cycloalkyl, heterocycloalkyl, –C1-6 alkyl–heterocycloalkyl, phenyl, –C1-6 alkyl–phenyl, heteroaryl, or –C1-6 alkyl–heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members and 1 to 3 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; alternatively, R4c and R4a together with the carbon and nitrogen to which each is attached combine to form a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, 3, or 4 R4a1; each R4c1 and R4c2 are independently C1-6 alkyl or C2-6 alkoxyalkyl; each R4a1 is independently C1-6 alkyl, –OH, –C1-6 alkyl–OH, C1-6 alkoxy, halo, or –N(R4a2)S(O)2–C1-4 alkyl; R4a2 is H or C1-6 alkyl; alternatively, two R4a1 groups on adjacent ring atoms combine to form a phenyl ring substituted with 0, 1, or 2 R4a3; each R4a3 is independently C1-6 alkyl, –OH, –C1-6 alkyl–OH, C1-6 alkoxy, or halo; X5 is a bond or –C(O)NR5d–; R5d is H or C1-6 alkyl; ring C is a heteroaryl having 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein the heteroaryl is substituted with 0, 1, 2, 3, or 4 R5e; each R5e is independently C1-6 alkyl, –OH, halo, C1-6 haloalkyl, or oxo; X6 is C6-7 alkylene or C6-7 alkenylene; R6b is H or C1-6 alkyl; R6d is H, C1-6 alkyl, C1-6 deuteroalkyl, –OH, or C2-6 alkoxyalkyl; R7a is H or C1-6 alkyl; R7b and R7c are each independently H, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 alkyl–OH, C3-6 cycloalkyl, or –C1-6 alkyl–C3-6 cycloalkyl; R8a is H, C1-6 alkyl, C1-6 deuteroalkyl, C2-6 alkoxyalkyl, C3-6 cycloalkyl, or –C1-6 alkyl–C3-6 cycloalkyl; R8b, R8d, and R8e are each independently H or C1-6 alkyl; PATENT Attorney Docket No.052687-509001WO alternatively R8b and R8d together with the carbon to which each is attached combine to form a C3-6 cycloalkyl; ring B is C6-12 aryl or heteroaryl having 5 to 12 ring members and 1 to 6 heteroatoms, each independently N, O, or S; the subscript m8 is 0, 1, 2, 3, 4, or 5; each R8f is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 deuteroalkoxy, C2-6 alkoxyalkyl, halo, C1-6 haloalkyl, C1-6 haloalkoxy, cyano, –X8f–cyano, –NR8f1R8f2, –C(O)NR8f1R8f2, –N(R8f1)C(O)R8f2, C3-12 cycloalkyl, –X8f–C3-6 cycloalkyl, heterocycloalkyl, –X8f–heterocycloalkyl, C6-12 aryl, –X8f–C 6-12 aryl, heteroaryl, or –X8f–heteroaryl, wherein each heterocycloalkyl has 3 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein each alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R8f3; alternatively, two R8f groups on adjacent ring vertices combine to form a C3-6 cycloalkyl or a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the cycloalkyl or heterocycloalkyl is substituted with 0, 1, 2, or 3 R8f3; each X8f is independently C1-6 alkylene, C2-6 alkenylene, –O–C1-6 alkylene, C(O), O, or S; each R8f1 and R8f2 are independently H or C1-6 alkyl; each R8f3 is independently C1-6 alkyl, –Y8–C1-6 alkyl, C1-6 deuteroalkyl, –Y8–C1-6 deuteroalkyl, –OH, –C1-6 alkyl–OH, –Y8–C1-6 alkyl–OH, –C1-6 alkyl–Y8–C1-6 alkyl, –(C1-2 alkyl–O)1-4–C1-2 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl, –Y8–C1-6 haloalkyl, cyano, –C1-6 alkyl–cyano, –C1-6 alkyl–NR8gR8h, oxo, C3-6 cycloalkyl, –X8f3–C3-6 cycloalkyl, heterocycloalkyl, –X8f3– heterocycloalkyl, phenyl, –X8f3–phenyl, heteroaryl, or –X8f3–heteroaryl, wherein each heterocycloalkyl has 3 to 12 members and 1 to 4 heteroatoms, each independently N, O, S, or S(O)2, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, and wherein each heterocycloalkyl and heteroaryl are substituted with 0, 1, or 2 C1-4 alkyl or halo; alternatively, two R8f3 groups on the same or adjacent ring vertices combine to form a C3-6 cycloalkyl or a heterocycloalkyl having 3 to 6 ring members and 1 to 3 PATENT Attorney Docket No.052687-509001WO heteroatoms, each independently N, O, or S, wherein nitrogen atom ring members in the heterocycloalkyl are substituted with 0 or 1 C1-4 alkyl; each X8f3 is independently C1-6 alkylene, O, C(O), or S(O)2; each Y8 is independently C(O), C(O)O, N(R8f4)C(O), O, S, or S(O)2; each R8g and R8h is independently H, C1-6 alkyl, or C1-6 haloalkyl; and each R8f4 is independently H or C1-6 alkyl; or a pharmaceutically acceptable salt thereof. [0040] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) having the structure of Formula (Ia): . [0041] R8f, and ring B can each independently be as defined for any embodiment of Formula (Ia) as described herein. Residue 3 [0042] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R3 is (a) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C1-6 haloalkyl substituted with 0, 1, 2, 3, 4, or 5 R3a. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R3 is (a) C1-6 alkyl or C1-6 haloalkyl substituted with 0, 1, or 2 R3a. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R3 is (a) C1-6 alkyl substituted with 0, 1, or 2 R3a. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R3 is (a) C1-6 haloalkyl substituted with 0, 1, or 2 R3a. These embodiments of R3 can be combined with any of the embodiments described herein for R3a. PATENT Attorney Docket No.052687-509001WO [0043] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R3a is –OH or C1-6 alkoxy. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R3a is –OH. These embodiments of R3a can be combined with any of the relevant embodiments described herein for R3. [0044] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R3 is (b) C3-12 cycloalkyl substituted with 0, 1, 2, or 3 R3b. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R3 is (b) C3-7 cycloalkyl substituted with 0, 1, 2, or 3 R3b. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R3 is (b) C5-6 cycloalkyl substituted with 0, 1, or 2 R3b. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R3 is (b) C3-4 cycloalkyl substituted with 0, 1, or 2 R3b. These embodiments of R3 can be combined with any of the embodiments described herein for R3b. [0045] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R3b is halo, C1-4 haloalkyl, or cyano. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R3b is halo or C1-4 haloalkyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R3b is fluoro or trifluoromethyl. These embodiments of R3b can be combined with any of the relevant embodiments described herein for R3. [0046] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R3 is (c) heterocycloalkyl having 3 to 6 ring 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 R3c. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R3 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 R3c. These embodiments of R3 can be combined with any of the relevant embodiments described herein for R3c. PATENT Attorney Docket No.052687-509001WO [0047] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R3c is halo or C1-4 haloalkyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R3c is fluoro or trifluoromethyl. These embodiments of R3c can be combined with any of the embodiments described herein for R3. [0048] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R3 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 R3g. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R3 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 R3g. These embodiments of R3 can be combined with any of the relevant embodiments described herein for R3g. [0049] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R3g is halo or C1-4 haloalkyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R3g is chloro, fluoro, or trifluoromethyl. These embodiments of R3g can be combined with any of the embodiments described herein for R3. [0050] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R3 is . [0051] Any of the can be combined with any of the embodiments described herein for residues 4, 5, 6, 7, and 8. For example, any of the embodiments of R3 as described herein, can be combined with any of the embodiments described herein for R4a, R4b, R4c, X5, ring C, R6b, X6, R6d, R7a, R7b, R7c, R8a, R8b, R8d, R8e, ring B, m8, and R8f. Residue 4 PATENT Attorney Docket No.052687-509001WO [0052] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R4a, R4b, and R4c are each independently H or C1-6 alkyl; alternatively, R4c and R4a 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 R4a1; and each R4a1 is independently halo. [0053] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R4a, R4b, and R4c are each independently H or C1-6 alkyl. [0054] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R4b is H or C1-6 alkyl; and R4c and R4a 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 R4a1. [0055] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R4a and R4b are each H; and R4c is ethyl; alternatively, R4c and R4a together with the carbon and nitrogen to which each is attached combine to form a pyrrolidinyl, substituted with 0, 1, or 2 fluoro. [0056] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R4b is H; and R4c and R4a together with the carbon and nitrogen to which each is attached combine to form a pyrrolidinyl, substituted with 0, 1, or 2 R4a1. [0057] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R4a1 is C1-6 alkyl or halo. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the PATENT Attorney Docket No.052687-509001WO compound of Formula (I) or (Ia), wherein R4a1 is halo. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R4a1 is fluoro. These embodiments of R4a1 can be combined with any of the relevant embodiments described herein for R4. [0058] The embodiments described herein for R4a, R4b and R4c can be present in any combination. In addition, the embodiments described herein for residue 4 can be present in combination with any of the embodiments described herein for residues 3, 5, 6, 7, and 8. For example, any of the embodiments of R4a, R4b and R4c as described herein, can be combined with any of the embodiments described herein for R3, X5, ring C, R6b, X6, R6d, R7a, R7b, R7c, R8a, R8b, R8d, R8e, ring B, m8, and R8f. Residue 5 [0059] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein X5 is a bond. [0060] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein X5 is –C(O)NR5d– [0061] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R5d is H. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R5d is C1-6 alkyl. [0062] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein ring C is 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, or 4 R5e. This embodiment of ring C can be combined with any of the embodiments described herein for X5. [0063] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein wherein ring C is heteroaryl having 9 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein the heteroaryl is substituted with 0, 1, 2, 3, or 4 R5e. This embodiment of ring C can be combined with any of the embodiments described herein for X5. PATENT Attorney Docket No.052687-509001WO [0064] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein ring C is a heteroaryl as defined above and is substituted with 0, 1, 2, or 3 R5e. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein ring C is a heteroaryl as defined above and is substituted with 0, 1, or 2 R5e. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein ring C is a heteroaryl as defined above and is substituted with 0 or 1 R5e. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein ring C is a heteroaryl as defined above and is substituted with 0 R5e. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein ring C is a heteroaryl as defined above and is substituted with 1 R5e. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein ring C is a heteroaryl as defined above and is substituted with 2 R5e. These embodiments of R5e can be combined with any of the embodiments described herein for ring C and X5. [0065] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R5e is independently C1-6 alkyl, –OH, halo, or oxo. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R5e is independently C1-6 alkyl or oxo. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R5e is independently halo or oxo. These embodiments of R5e can be combined with any of the embodiments described herein for ring C and X5. [0066] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein ring C is . These herein for X5. PATENT Attorney Docket No.052687-509001WO [0067] Certain ring C moieties can exist as tautomers. All possible tautomers are within the scope of this disclosure. For example, an oxo substituted ring C moiety can exist as a tautomer as shown below: . [0068] The embodiments C can be present in any combination. In addition, the embodiments described herein for residue 5 can be present in combination with any of the embodiments described herein for residues 3, 4, 6, 7, and 8. For example, any of the embodiments of X5 and ring C as described herein, can be combined with any of the embodiments described herein for R3, R4a, R4b, R4c, R6b, X6, R6d, R7a, R7b, R7c, R8a, R8b, R8d, R8e, ring B, m8, and R8f. Residue 6 [0069] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein X6 is C6-7 alkylene. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein X6 is C6-7 alkenylene. These embodiments of X6 can be combined with any of the embodiments described herein for R6b and R6d. [0070] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein X6 is . This embodiment of X6 can be the embodiments described herein for R6b and R6d. [0071] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein X6 is PATENT Attorney Docket No.052687-509001WO , wherein the wavy bond attached to E, Z, or a mixture of both isomers. This embodiment of X6 can any of the embodiments described herein for R6b and R6d. [0072] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R6b and R6d are each independently H or C1-6 alkyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R6b is H; and R6d is C1-4 alkyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R6b and R6d are each H. These embodiments of R6b and R6d can be combined with any of the embodiments described herein for X6. [0073] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R6b is H; and R6d is H, methyl, or ethyl. This embodiment of R6b and R6d can be combined with any of the embodiments described herein for X6. [0074] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R6b is H; and R6d is H or methyl. This embodiment of R6b and R6d can be combined with any of the embodiments described herein for X6. [0075] The embodiments described herein for X6, R6b and R6d can be present in any combination. In addition, 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. For example, any of the embodiments of X6, R6b and R6d as described herein, can be combined with any of the embodiments described herein for R3, R4a, R4b, R4c, X5, ring C, R7a, R7b, R7c, R8a, R8b, R8d, R8e, ring B, m8, and R8f. PATENT Attorney Docket No.052687-509001WO Residue 7 [0076] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R7a and R7b are each independently H or C1- 6 alkyl; and R7c is C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 alkyl–OH, or –C1-6 alkyl–C3-6 cycloalkyl. [0077] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R7a and R7b are each independently H or C1- 6 alkyl; and R7c is C1-6 alkyl, C3-6 cycloalkyl, or –C1-6 alkyl–C3-6 cycloalkyl. [0078] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R7a and R7b are each independently H or C1- 6 alkyl; and R7c is C1-6 alkyl or C1-6 haloalkyl. [0079] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R7a and R7b are each H; and R7c is C1-6 alkyl. [0080] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R7a and R7b are each H; and R7c is isobutyl, . or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R7a and R7b are each H; and R7c is isobutyl. [0082] The embodiments described herein for R7a, R7b and R7c can be present in any combination. In addition, the embodiments described herein for residue 7 can be present in combination with any of the embodiments described herein for residues 3, 4, 5, 6, and 8. For example, any of the embodiments of R7a, R7b and R7c as described herein, can be combined with any of the embodiments described herein for R3, R4a, R4b, R4c, X5, ring C, R6b, X6, R6d, R8a, R8b, R8d, R8e, ring B, m8, and R8f. Residue 8 [0083] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R8a, R8b, R8d, and R8e are each PATENT Attorney Docket No.052687-509001WO independently H or C1-6 alkyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R8a is H or methyl; and R8b, R8d and R8e are each H. These embodiments of R8a, R8b, R8d, and R8e can be combined with any of the embodiments described herein for m8, ring B, R8f, and R8f3. [0084] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), 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. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein ring B is phenyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein ring B is biphenyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), 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. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein ring B is a heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, wherein each heteroatom is N. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein ring B is pyridyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein ring B is pyrid-3-yl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein ring B is phenyl or pyridyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), 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 R8a, R8b, R8d, R8e, m8, R8f, and R8f3. [0085] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein the subscript m8 is 1, 2, or 3. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein the subscript m8 is 0. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein the subscript m8 is 1. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein the subscript m8 is 2. In some embodiments, the compound, or the pharmaceutically acceptable PATENT Attorney Docket No.052687-509001WO salt thereof, is the compound of Formula (I) or (Ia), wherein the subscript m8 is 3. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein the subscript m8 is 4. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein the subscript m8 is 5. These embodiments of m8 can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, R8f, R8f3, and ring B. [0086] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein the moiety . These embodiments described herein for R8a, R8b, R8d, R8e, R8f, R8f3, m8 and ring B. [0087] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein the moiety . These embodiments herein for R8a, R8b, R8d, R8e, R8f, R8f3, m8 and ring B. [0088] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein the moiety . PATENT Attorney Docket No.052687-509001WO These embodiments can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, R8f, R8f3, m8 and ring B. [0089] In some embodiments, at least one R8f is halo. In some embodiments, at least one R8f is fluoro or chloro. These embodiments of R8f can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f3. [0090] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R8f is independently C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C1-6 deuteroalkoxy, halo, C1-6 haloalkyl, cyano, or –X8f–cyano. These embodiments of R8f can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f3. [0091] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R8f is independently halo, C3-6 cycloalkyl, –X8f–C3-6 cycloalkyl, –CH=CR8f5R8f6, heterocycloalkyl, –X8f–heterocycloalkyl, phenyl, –X8f–phenyl, heteroaryl, or –X8f–heteroaryl, wherein each heterocycloalkyl has 3 to 10 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is substituted with 0, 1, 2 or 3 R8f3; each X8f is independently C1-6 alkylene, C2-6 alkenylene, O, or S; and each R8f5 and R8f6 are combined with the carbon to which they are attached to form a heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms, each independently N, O or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, or 3 R8f3. These embodiments of R8f can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f3. [0092] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R8f is independently halo, C3-6 cycloalkyl, –X8f–C3-6 cycloalkyl, –CH=CR8f5R8f5, heterocycloalkyl, –X8f–heterocycloalkyl, heteroaryl, or –X8f–heteroaryl, wherein each heterocycloalkyl has 3 to 10 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein each cycloalkyl, heterocycloalkyl, and heteroaryl is substituted with 0, 1, 2, or 3 R8f3; each X8f is independently C1-6 alkylene, C2-6 alkenylene, O, or S; and each R8f5 and R8f6 are combined with the carbon to which they are attached to form a heterocycloalkyl having 3 to 10 ring PATENT Attorney Docket No.052687-509001WO members and 1 to 3 heteroatoms, each independently N, O or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, or 3 R8f3. These embodiments of R8f can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f3. [0093] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each X8f is independently C1-6 alkylene. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each X8f is independently C2-6 alkenylene. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each X8f is independently –O–C1-6 alkylene. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each X8f is independently O. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each X8f is independently S. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each X8f is independently C1-6 alkylene or O. These embodiments of R8f can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f3. [0094] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R8f is independently halo, C3-6 cycloalkyl, –CH=CR8f5R8f6, heterocycloalkyl, phenyl, or heteroaryl, wherein each heterocycloalkyl has 3 to 10 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is substituted with 0, 1, 2, or 3 R8f3; each R8f5 and R8f6 are combined with the carbon to which they are attached to form a heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms, each independently N, O or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, or 3 R8f3. These embodiments of R8f can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f3. [0095] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R8f is independently C1-4 alkyl, C2-4 alkenyl, C1-4 alkoxy, C1-4 deuteroalkoxy, halo, C1-4 haloalkyl, cyano, or –C1-2 alkyl– PATENT Attorney Docket No.052687-509001WO cyano. These embodiments of R8f can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f3. [0096] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R8f is independently halo, C3-6 cycloalkyl, –O–C3-6 cycloalkyl, heterocycloalkyl, –C2-4 alkenyl–heterocycloalkyl, –O–heterocycloalkyl, –CH=CR8f5R8f6, phenyl, –O–phenyl, heteroaryl, or –O–heteroaryl, wherein each heterocycloalkyl has 3 to 9 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 9 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is substituted with 0, 1, 2, or 3 R8f3; and R8f5 and R8f6 are combined with the carbon to which they are attached to form a heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms, each independently N, O or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, or 3 R8f3. These embodiments of R8f can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f3. [0097] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R8f is independently halo, C3-6 cycloalkyl, –O–C3-6 cycloalkyl, heterocycloalkyl, –C2-4 alkenyl–heterocycloalkyl, –O– heterocycloalkyl, phenyl, –O–phenyl, heteroaryl, or –O–heteroaryl, wherein each 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, heterocycloalkyl, phenyl, and heteroaryl is substituted with 0, 1, 2, or 3 R8f3. These embodiments of R8f can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f3. [0098] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R8f is independently halo, C3-6 cycloalkyl, –O–C3-6 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 R8f3. These embodiments of R8f can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f3. [0099] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R8f is independently halo, PATENT Attorney Docket No.052687-509001WO heterocycloalkyl, –O–heterocycloalkyl, phenyl, or –O–phenyl, wherein each heterocycloalkyl 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 R8f3. These embodiments of R8f can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f3. [0100] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R8f 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 heterocycloalkyl is substituted with 0, 1, 2, or 3 R8f3. These embodiments of R8f can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f3. [0101] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R8f3 is C1-6 alkyl, –Y8–C1-6 alkyl, C1-6 deuteroalkyl, –Y8–C1-6 deuteroalkyl, –OH, –C1-6 alkyl–OH, –Y8–C1-6 alkyl–OH, –C1-6 alkyl–Y8–C1-6 alkyl, –(C1-2 alkyl–O)2-4–C1-2 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl, – Y8–C1-6 haloalkyl, cyano, –C1-6 alkyl–cyano, –C1-6 alkyl–NR8gR8h, oxo, C3-6 cycloalkyl, – X8f3–C3-6 cycloalkyl, heterocycloalkyl, –X8f3– heterocycloalkyl, phenyl, –X8f3–phenyl, heteroaryl, or –X8f3–heteroaryl, wherein each heterocycloalkyl has 3 to 12 members and 1 to 4 heteroatoms, each independently N, O, S, or S(O)2, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, and wherein each heterocycloalkyl and heteroaryl are substituted with 0, 1, or 2 C1-4 alkyl or halo. [0102] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R8f3 is independently C1-6 alkyl, –Y8–C1-6 alkyl, C1-6 deuteroalky, –Y8–C1-6 deuteroalkyl, –OH, –C1-6 alkyl–OH, –Y8–C1-6 alkyl–OH, –C1-6 alkyl–Y8–C1-6 alkyl, halo, C1-6 haloalkyl, –Y8–C1-6 haloalkyl, or oxo; each Y8 is independently C(O), C(O)O, N(R8f4)C(O), O, S, or S(O)2; and each R8f4 is independently H or C1-6 alkyl. These embodiments of R8f3 can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f. [0103] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each Y8 is independently –Y8–C1-6 alkyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, PATENT Attorney Docket No.052687-509001WO is the compound of Formula (I) or (Ia), wherein each Y8 is independently –Y8–methyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each Y8 is independently C(O). In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each Y8 is independently C(O)O. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each Y8 is independently NHC(O). In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each Y8 is independently O. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each Y8 is independently S. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each Y8 is independently S(O)2. These embodiments of Y8 can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, R8f, and R8f3. [0104] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R8f3 is independently C1-6 alkyl, C1-6 deuteroalky, –OH, –C1-6 alkyl–OH, halo, C1-6 haloalkyl, or oxo. These embodiments of R8f3 can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f. [0105] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R8f3 is independently C1-6 alkyl or –Y8–C1-6 alkyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each Y8 is independently a C(O) or C(O)O. These embodiments of R8f3 and Y8 can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f. [0106] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R8f3 is independently C3-6 cycloalkyl, –X8f3–C3-6 cycloalkyl, heterocycloalkyl, or –X8f3–heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 members and 1 to 2 heteroatoms, each independently N, O, S, or S(O)2; and each X8f3 is independently C1-6 alkylene, C(O), or S(O)2. These embodiments of PATENT Attorney Docket No.052687-509001WO R8f3 can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f. [0107] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each X8f3 is independently C1-6 alkylene. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each X8f3 is independently C(O). In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each X8f3 is independently S(O)2. These embodiments of X8f3 can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, R8f, and R8f3. [0108] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R8f3 is independently C3-6 cycloalkyl or heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 members and 1 to 2 heteroatoms, each independently N, O, S, or S(O)2. These embodiments of R8f3 can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f. [0109] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein two R8f3 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. These embodiments of R8f3 can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f. [0110] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R8f3 is independently C1-4 alkyl, C1-4 alkoxy, C2-6 alkoxyalkyl, –S(O)2–C1-4 alkyl, –C1-4 alkyl–S(O)2–C1-4 alkyl, halo, C1-4 haloalkyl, oxo, –C(O)–C1-4 alkyl, or –C(O)O–C1-4 alkyl. These embodiments of R8f3 can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f. [0111] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein each R8f3 is independently C1-4 alkyl, C1-4 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)–C1-4 alkyl, –C(O)O–C1-4 alkyl, C3-6 cycloalkyl, –C(O)–C3-6 cycloalkyl, – S(O)2–C3-6 cycloalkyl, heterocycloalkyl, –C1-4 alkyl–heterocycloalkyl, or –S(O)2– PATENT Attorney Docket No.052687-509001WO heterocycloalkyl, wherein each heterocycloalkyl has 4 to 6 members and 1 to 2 heteroatoms, each independently N, O, S, or S(O)2; alternatively, two R8f3 groups on adjacent ring vertices combine to form a non-aromatic cyclic moiety having 3 to 6 ring members and 0 to 2 additional heteroatoms, each independently N, O or S. These embodiments of R8f3 can be combined with any of the embodiments described herein for R8a, R8b, R8d, R8e, m8, ring B, and R8f. [0112] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein m8 is 2; and each R8f is independently fluoro, chloro, bromo, , [0113] thereof, is the compound of Formula (I) or (Ia), wherein m8 is 2; and each R8f is independently chloro, bromo, , PATENT Attorney Docket No.052687-509001WO [0114] The embodiments described herein for R8a, R8b, R8d, R8e, m8 and R8f can be present in any combination. In addition, the embodiments described herein for residue 8 can be present in combination with any of the embodiments described herein for residues 3, 4, 5, 6, and 7. For example, any of the embodiments of R8a, R8b, R8d, R8e, ring B, m8 and R8f as described herein, can be combined with any of the embodiments described herein for R3, R4a, R4b, R4c, X5, ring C, R6b, X6, R6d, R7a, R7b, and R7c. Residues 3 to 8 [0115] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia), wherein R3 is ; R4b is R4c and R4a together with the carbon and nitrogen to which each is attached combine to form a pyrrolidinyl, wherein the pyrrolidinyl is substituted with 0 or 1 fluoro; X5 is a bond or –C(O)NH–; ring C is ; X6 is ; R6b is R6d is H or methyl; R7a is H; R7b is H; PATENT Attorney Docket No.052687-509001WO R7c is isobutyl; R8a is methyl; R8b, R8d and R8e are each H; ring B is phenyl, biphenyl, or pyridyl; m8 is 2; and each R8f is independently fluoro, chloro, bromo, , [0116] thereof, is the compound of Formula (I) or (Ia), wherein R3 is ; R4b is R4c and R4a together with the carbon and nitrogen to which each is attached combine to form a pyrrolidinyl, wherein the pyrrolidinyl is substituted with 0 or 1 fluoro; X5 is a bond or –C(O)NH–; ring C is ; PATENT Attorney Docket No.052687-509001WO X6 is ; R6b is 6d R is R7a is H; R7b is H; R7c is isobutyl; R8a is methyl; R8b, R8d and R8e are each H; ring B is phenyl, biphenyl, or pyridyl; m8 is 2; and each R8f is independently chloro, bromo, , [0117] R7c, R8a, R8b, R8d, R8e, ring B, m8, and R8f can each independently be as defined for any embodiment of Formula (I) or (Ia) as described herein. [0118] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (Ia) having the structure of any one of Examples 1-36. [0119] 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 PATENT Attorney Docket No.052687-509001WO of Formula (I) or (Ia) can have asymmetric centers at one or more carbon atoms, and therefore compounds of Formula (I) or (Ia) can exist in diastereomeric or enantiomeric forms or mixtures 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) or (Ia) can be prepared using diastereomers, enantiomers or racemic mixtures as starting materials. Furthermore, diastereomer and enantiomer products can be separated by chromatography, fractional crystallization or other methods known to those of skill in the art. Unless otherwise indicated, when a stereochemical depiction is shown, 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. When a structure includes a wavy bond attached to a double bond, this indicates E, Z, or a mixture of both isomers. [0120] The compounds of Formula (I) or (Ia) can also be in the salt forms, such as acid or base salts of the compounds of Formula (I) or (Ia). 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, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference. [0121] Pharmaceutically acceptable salts of the acidic compounds of Formula (I) or (Ia) are salts 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. [0122] Similarly acid addition salts, such as of mineral acids, organic carboxylic and 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. [0123] 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 PATENT Attorney Docket No.052687-509001WO 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 compound for the purposes of the present disclosure. [0124] The present disclosure also includes isotopically-labeled compounds of Formula (I) or (Ia), wherein one or more atoms are replaced by one or more atoms having specific atomic mass or mass numbers. Examples of isotopes that can be incorporated into compounds of Formula (I) or (Ia) include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 18F, 35S and 36Cl). Isotopically-labeled compounds of Formula (I) or (Ia) can be useful in assays of the tissue distribution of the compounds and their prodrugs and metabolites; preferred isotopes for such assays include 3H and 14C. In addition, in certain circumstances substitution with heavier isotopes, such as deuterium (2H), can provide increased metabolic stability, which offers therapeutic advantages such as increased in vivo half-life or reduced dosage requirements. Isotopically-labeled compounds of Formula (I) or (Ia) can generally be prepared according to methods known in the art. IV. Compositions [0125] The compounds of Formula (I) or (Ia) described herein are useful in the manufacture of a pharmaceutical composition or a medicament for modulating one or more cyclins (e.g. cyclin A, cyclin B, cycline E). In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, and a pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition or medicament comprising one or more compounds of Formula (I) or (Ia) can be administered to a subject for the treatment of a cancer. [0126] 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. Martin. Compounds of Formula (I) or (Ia) 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, subcutaneously, intramuscularly, etc.), and combinations thereof. In some embodiments, the compounds of Formula (I) or (Ia) is dissolved in a liquid, for example, water. The most PATENT Attorney Docket No.052687-509001WO suitable route of administration for a compound of Formula (I) or (Ia) in any given case will depend, in part, on the nature, severity, and optionally, and the stage of the cancer. [0127] The pharmaceutical compositions or medicaments of the present disclosure can include a compound of Formula (I) or (Ia) 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) or (Ia) disclosed herein. [0128] In some embodiments, 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). In some embodiments, the pharmaceutical compositions or medicaments can be administered via a syringe or intravenously. In preferred embodiments, the pharmaceutical compositions or medicaments are injected subcutaneously. [0129] For oral administration, 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. Preferred are tablets and gelatin capsules comprising the active 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, 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 carboxymethylcellulose, polyvinylpyrrolidone and/or hydroxypropyl methylcellulose; if desired (d) disintegrants, e.g., starches (e.g., potato starch or sodium starch), glycolate, agar, alginic acid or its sodium salt, or effervescent mixtures; (e) wetting agents, e.g., sodium lauryl sulfate, and/or (f) absorbents, colorants, flavors and sweeteners. In some embodiments, the tablet contains a mixture of hydroxypropyl methylcellulose, polyethyleneglycol 6000 and titatium dioxide. Tablets can be either film coated or enteric coated according to methods known in the art. PATENT Attorney Docket No.052687-509001WO [0130] 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 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 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. [0131] Typical formulations for topical administration include creams, ointments, sprays, 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), or for oral, rectal, or vaginal administration is also contemplated. [0132] Pharmaceutical 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 inhaler device known to a person skilled in the art. In certain instances, 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. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to 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. PATENT Attorney Docket No.052687-509001WO [0133] The compounds of Formula (I) or (Ia) 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. [0134] The compounds of Formula (I) or (Ia) set forth herein can be formulated for parenteral 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, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. Alternatively, the compound(s) can be in powder form for reconstitution with a suitable vehicle, for example, sterile pyrogen-free water, before use. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the compound(s). [0135] In some embodiments, 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. [0136] In some embodiments, the compositions described herein further include a pharmaceutical surfactant. In other embodiments, the compositions further include a cryoprotectant. Non-limiting examples of cryoprotectants include glucose, sucrose, trehalose, lactose, sodium glutamate, PVP, cyclodextrin, 2-hydroxypropyl-13-cyclodextrin (HPI3CD) glycerol, maltose, mannitol, saccharose, and mixtures thereof. V. Methods [0137] The present disclosure contemplates the use of the compounds of Formula (I) or (Ia) described herein in the treatment or prevention of diseases or disorders modulated, at least in part, by one or more cyclins. In some embodiments, the cyclin mediated disease is a proliferative condition or disorder, including cancer. In some embodiments, the present disclosure provides a method of treating a cancer mediated at least in part by cyclin activity, PATENT Attorney Docket No.052687-509001WO 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. [0138] In some embodiments, provided herein are compounds of Formula (I) or (Ia) for use in therapy. [0139] The present disclosure contemplates the use of the compounds of Formula (I) or (Ia) described herein in the treatment or prevention of diseases or disorders modulated, at least in part, by cyclin A. In some embodiments, the cyclin A mediated disease is a proliferative condition or disorder, including cancer. In some embodiments, the present disclosure 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. [0140] In some embodiments, provided herein are methods of treating a proliferative condition or disorder mediated at least in part by cyclin A comprising administering a compound of Formula (I) or (Ia) described herein. [0141] In some embodiments, provided herein are compounds of Formula (I) or (Ia) for use in a method for treating a proliferative condition or disorder mediated at least in part by cyclin A. [0142] In some embodiments, provided herein are uses of compounds of Formula (I) or (Ia) for the manufacture of a medicament for the treatment of a proliferative condition or disorder mediated at least in part by cyclin A. [0143] The present disclosure contemplates the use of the compounds of Formula (I) or (Ia) described herein in the treatment or prevention of diseases or disorders modulated, at least in part, by cyclin B. In some embodiments, the cyclin B mediated disease is a proliferative condition or disorder, including cancer. In some embodiments, 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. PATENT Attorney Docket No.052687-509001WO [0144] In some embodiments, provided herein are methods of treating a proliferative condition or disorder mediated at least in part by cyclin B comprising administering a compound of Formula (I) or (Ia) described herein. [0145] In some embodiments, provided herein are compounds of Formula (I) or (Ia) for use in a method for treating a proliferative condition or disorder mediated at least in part by cyclin B. [0146] In some embodiments, provided herein are uses of compounds of Formula (I) or (Ia) for the manufacture of a medicament for the treatment of a proliferative condition or disorder mediated at least in part by cyclin B. [0147] The present disclosure contemplates the use of the compounds Formula (I) or (Ia) described herein in the treatment or prevention of diseases or disorders modulated, at least in part, by cyclin E. In some embodiments, the cyclin E mediated disease is a proliferative condition or disorder, including cancer. In some embodiments, 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 compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, thereby treating the cancer. [0148] In some embodiments, provided herein are methods of treating a proliferative condition or disorder mediated at least in part by cyclin E comprising administering a compound of Formula (I) or (Ia) described herein. [0149] In some embodiments, provided herein are compounds of Formula (I) or (Ia) for use in a method for treating a proliferative condition or disorder mediated at least in part by cyclin E. [0150] In some embodiments, provided herein are uses of compounds of Formula (I) or (Ia) for the manufacture of a medicament for the treatment of a proliferative condition or disorder mediated at least in part by cyclin E. [0151] In some embodiments, the compounds of Formula (I) or (Ia) described herein can be used to treat or prevent a proliferative condition or disorder, including 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- PATENT Attorney Docket No.052687-509001WO small-cell lung carcinoma, small cell lung cancer), pancreas, salivary gland, adrenal gland, thyroid, brain, ganglia, central nervous system (CNS) and peripheral nervous system (PNS), and cancers of the hematopoietic system and the immune system (e.g., spleen or thymus). [0152] 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., 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. [0153] In some embodiments, the tumor or cancer is colon cancer, ovarian cancer, breast cancer, melanoma, lung cancer, glioblastoma, or leukemia. [0154] In some embodiments, the tumor or cancer is small cell lung cancer (SCLC). [0155] 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. [0156] In some embodiments, the cancer is a blood cancer (e.g., leukemia, lymphoma, multiple myeloma). [0157] In some embodiments, the leukemia is acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, or hairy cell leukemia. [0158] In some embodiments, the lymphoma is non-Hodgkin's lymphoma, Hodgkin's lymphoma, B-cell lymphoma, or Burkitt's lymphoma. [0159] In some embodiments, the cancer is an Rb mutated cancer. In some embodiments, the cancer has a mutation in the Rb/E2F pathway. VI. Administration [0160] The present disclosure contemplates the administration of compounds of Formula (I) or (Ia) 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, PATENT Attorney Docket No.052687-509001WO intracerebral (intraparenchymal) and intracerebroventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal and inhalation. [0161] Pharmaceutical compositions comprising compounds of Formula (I) or (Ia) are preferably in unit dosage form. The unit dosage form can be a packaged preparation, the package 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. [0162] Compounds of Formula (I) or (Ia) or pharmaceutical compositions or medicaments thereof can be administered to a subject diagnosed or suspected of having a disease or disorder mediated at least in part by cyclin A in an amount sufficient to elicit an effective therapeutic response in the subject. [0163] 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. The size of the dose will also be determined by the existence, nature, and extent of any adverse effects that accompany the administration of a particular compound in a particular subject. Typically, 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 optimum dosages, dosing methodologies, and repetition rates. [0164] In some embodiments, a unit dosage for oral administration of a compound of Formula (I) or (Ia) 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). [0165] In some embodiments, a unit dosage for subcutaneous administration of a compound of Formula (I) or (Ia) 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. [0166] The dose can be administered once per day or divided into sub-doses and administered in multiple doses, e.g., twice, three times, or four times per day. However, as PATENT Attorney Docket No.052687-509001WO will be appreciated by a skilled artisan, depending on the route of administration different amounts can be administered at different times. [0167] In some embodiments, 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 weeks, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more weeks. In some embodiments, 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. [0168] 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 pharmaceutical procedures in experimental animals, for example, by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (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, LD50/ED50. Compounds that exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side-effects can be used, care should be taken to design a delivery system that targets such compounds to the affected site to minimize potential damage to normal cells and, thereby, reduce side-effects. [0169] The dosage of a pharmaceutical composition or medicament of the present disclosure can be monitored and adjusted throughout treatment, depending on severity of symptoms, frequency of recurrence, and/or the physiological response to the therapeutic regimen. Those of skill in the art commonly engage in such adjustments in therapeutic regimens. [0170] 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 sufficient quantity of the compounds of the disclosure to effectively treat the patient. Generally, when treating cancer, the dose is sufficient to stop tumor growth or cause tumor regression without producing unacceptable toxicity or side-effects to the patient. VII. Intermediates [0171] In some embodiments, the present disclosure provides intermediates useful in the preparation of compounds of Formula (I). Certain intermediates useful in the preparation of a PATENT Attorney Docket No.052687-509001WO compound of Formula (I) can be found, for example, in the Examples section of the current disclosure. [0172] In some embodiments, the intermediate is an External Building Block described herein. In some embodiments the intermediate is a compound produced in Method A, Mathod B, or one of Methods 1-4 for any one of the compounds exemplified herein. In some embodiments, the intermediate is one of Int.1-30. [0173] In some embodiments, the intermediate is a combination of one or more covalently linked External Building Blocks. VIII. Kits [0174] The present disclosure contemplates kits comprising a compound of Formula (I) or (Ia) 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. [0175] A kit can include one or more of the compounds disclosed herein (provided in, e.g., 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. When the compounds described herein are in a form that needs to be reconstituted or diluted by a user, the kit may also include diluents (e.g., sterile water), buffers, pharmaceutically acceptable excipients, and the like, packaged with or separately from the compounds described herein. Each component of the kit can be enclosed within an individual container, and all of the various containers can be within a single package. A kit of the present disclosure can be designed for conditions necessary to properly maintain the components housed therein (e.g., refrigeration or freezing). [0176] 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 include manufacturer information such as lot numbers and expiration dates. The label or packaging insert may be, e.g., integrated into the physical structure housing the components, PATENT Attorney Docket No.052687-509001WO contained separately within the physical structure, or affixed to a component of the kit (e.g., an ampule, tube or vial). [0177] 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 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. In some embodiments, 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. IX. Examples [0178] 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 [0179] 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. The order and details related to covalently linking these external building blocks are described in another section. Table 1: External Building Blocks of the Present Disclosure INT # IUPAC CAS Number, if known Int.1 hex-5-en-1-amine 34825-70-2 Int.2 N-Methylhex-5-en-1-amine 55863-02-0 Int.3 (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3- (2,5-dichlorophenyl)propanoic acid Int.4 (S)-3-(2-bromo-5-chlorophenyl)-2-((tert- butoxycarbonyl)(methyl)amino)propanoic acid Int.5 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- 761446-44-0 dioxaborolan-2-yl)-1H-pyrazole Int.6 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2- 1151802-22-0 dioxaborolan-2-yl)-1H-pyrazole Int.7 (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3- (5-chloro-2-cyclopropoxypyridin-3-yl)propanoic acid PATENT Attorney Docket No.052687-509001WO Int.8 1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2- 1002309-48-9 dioxaborolan-2-yl)-1H-pyrazole Int.9 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2- 1257554-02-1 dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine Int.10 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1314137-24-0 [1,2,4]triazolo[4,3-a]pyridine Int.11 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- 1227068-67-8 yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one Int.12 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- 1314138-13-0 yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one Int.13 (S)-3-(2-bromo-5-fluorophenyl )-2-((tert- butoxycarbonyl)(methyl)amino)propanoic acid Int.14 1-(tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl- 1029715-63-6 1,3,2-dioxaborolan-2-yl)-1H-pyrazole Int.15 (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3- (5-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridine- 3-yl)propanoic acid Int.16 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2- 944994-03-0 dioxaborolan-2-yl)-1H-pyrazole Int.17 (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3- (5-chloro-2-(cyclopropylthio)pyridin-3- yl)propanoic acid Int.18 1-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl- 1612172-62-9 1,3,2-dioxaborolan-2-yl)-1H-pyrazole Int.19 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- 485799-04-0 yl)pyridin-2-yl)morpholine Int.20 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2- 747413-21-4 dioxaborolan-2-yl)phenyl)piperazine Int.21 (2S,6S)-2,6-dimethyl-4-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)morpholine Int.22 (2S,4R)-1-(3,3-difluoro-1- (trifluoromethyl)cyclobutane-1-carbonyl)-4- fluoropyrrolidine-2-carboxylic acid Int.23 (2S,4R)-4-fluoro-1-(1- (trifluoromethyl)cyclobutane-1- carbonyl)pyrrolidine-2-carboxylic acid Int.24 (2S,4R)-4-fluoro-1-((R)-2- (trifluoromethyl)tetrahydro-2H-pyran-2- carbonyl)pyrrolidine-2-carboxylic acid Int.25 (S)-2-(2-((2S,4R)-1-(3,3-difluoro-1- (trifluoromethyl)cyclobutane-1-carbonyl)-4- fluoropyrrolidin-2-yl)-4-oxo-3,4-dihydro-5H- imidazo[4,5-c]pyridin-5-yl)pent-4-enoic acid Int.27 (S)-2-(3-((tert-butoxycarbonyl)amino)-5-methyl- 2-oxopyridin-1(2H)-yl)pent-4-enoic acid Int.28 (S)-2-(3-((tert-butoxycarbonyl)amino)-6-methyl- 2-oxopyridin-1(2H)-yl)pent-4-enoic acid Int.29 (S)-2-(3-((tert-butoxycarbonyl)amino)-5-chloro- 2-oxopyridin-1(2H)-yl)pent-4-enoic acid PATENT Attorney Docket No.052687-509001WO Int.30 (S)-2-(3-((tert-butoxycarbonyl)amino)-2- oxopyridin-1(2H)-yl)pent-4-enoic acid Int.3: Preparation of (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(2,5- dichlorophenyl)propanoic acid Step 1: Methyl (2S)-2-[(tert- (2,5-dichlorophenyl)propanoate: [0180] To a (1.33 g, 12.28 mmol, 0.067 eq) in DMA was added methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3- iodopropanoate (1.03 g, 3.11 mmol, 1.7 eq) dropwise below 45 ℃ under nitrogen atmosphere. The resulting mixture was stirred for 16 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)Cl2.CH2Cl2 (14.93 g, 18.32 mmol, 0.10 eq) at rt under nitrogen. The resulting mixture was stirred for additional 16 h at 85 ℃. Desired product could be detected by LCMS. The reaction was quenched by the addition of water (1.5 L) at rt. The aqueous layer was extracted with EtOAc (3 x 500 mL). The combined organics were washed with (5 x 300 mL) of water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (25:1) to afford methyl (2S)-2-[(tert- butoxycarbonyl)amino]-3-(2,5-dichlorophenyl)propanoate (40 g, 63 %) as a white solid. LCMS (ESI+): m/z 292.15 (M-56+).1H NMR (300 MHz, DMSO-d6): δ 1.11 – 1.47 (m, 12H), 2.89 (dd, 1H), 3.22 (dd, 1H), 3.64 (d, 4H), 3.91 – 4.37 (m, 1H), 6.87 – 7.89 (m, 4H). Step 2: Methyl (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2,5- dichlorophenyl)propanoate: PATENT Attorney Docket No.052687-509001WO [0181] 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 ℃ under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 25 ℃. 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 (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 Na2SO4. 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. This resulted in methyl (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2,5- dichlorophenyl)propanoate as a white solid. LCMS (ESI+): m/z 262.20 (M+Na+). Step 3: Int.3: [0182] dichlorophenyl)propanoate (35 g, 96.62 mmol, 1 eq) and LiOH (4.63 g, 193.24 mmol, 2 eq) in THF (500 mL)/ H2O (300 mg) was stirred for 16 h at 25 ℃. Desired product could be detected by LCMS. The mixture was acidified to pH=4 with diluted HCl (aq.). The aqueous layer was extracted with EtOAc (3 x 500 mL). The combined organics 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 (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 220 nm. This resulted in Int.3 (25.26 g, 75.07%) as a light-yellow solid. LCMS (ESI+): m/z 346.00 (M-H-).1H NMR (400 MHz, PATENT Attorney Docket No.052687-509001WO DMSO-d6): δ 1.23 (d, 9H), 2.66 (d, 3H), 3.06 – 3.39 (m, 2H), 7.24 – 7.56 (m, 3H), 13.00 (s, 1H). Int.4: Preparation of (S)-3-(2-bromo-5-chlorophenyl)-2-((tert- butoxycarbonyl)(methyl)amino)propanoic acid Step 1: (2S,5R)-2-(2-bromo-5- 5-isopropyl-2,5- dihydropyrazine: [0183] To (151 g, 711 mmol, 1.00 eq) in THF (1500 mL) was added n-BuLi (2.5 M, 285 mL, 1.00 eq) at -70 °C under N2, then to the above solution was added 1-bromo-2-(bromomethyl)-4-chlorobenzene (222.5 g, 782 mmol, 1.10 eq) in THF (220 mL) at -70 °C. The mixture was stirred at 25 °C for 12 hours. TLC indicated 1-bromo-2-(bromomethyl)-4-chlorobenzene was remained, and some new spots was detected. The reaction was poured into sat. NH4Cl (aq.) 6000 mL, the reaction mixture was partitioned between water phase 6000 mL and THF 6000 mL. The organic phase was separated and dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EtOAc=100/0 to 1/1) to give desired (2S,5R)-2-(2-bromo-5-chlorobenzyl)-3,6-diethoxy- 5-isopropyl-2,5-dihydropyrazine (620 g, 1.48 mol, 104 % yield, 99.3% purity) as a yellow gum. LCMS (ESI+): m/z 415/417 (M+H+) Step 2: Ethyl (S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoate: PATENT Attorney Docket No.052687-509001WO [0184] To a 5-isopropyl-2,5- dihydropyrazine (100 g, 240 mmol, 1.00 eq) in ACN (1500 mL) was added HCl (0.20 M, 1.40 L, 1.16 eq) at 0 °C, then was stirred at 25 °C for 48 hours. TLC indicated (2S,5R)-2-(2- bromo-5-chlorobenzyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine was consumed completely. The reaction mixture was concentrated under reduced pressure to remove ACN and extracted with DCM 4000 mL (2000 mL x 2), the organic layers was concentrated under reduced pressure to give a residue. Then the water phase was basified with sat.aq. NaHCO3 to pH=7 and extracted with DCM 4.00 L (2.00 L x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give desired ethyl (S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoate (143 g, 466 mmol, 49 % yield) as a white solid and to give (2S,5R)-2-(2-bromo-5-chlorobenzyl)-3,6-diethoxy-5-isopropyl-2,5- dihydropyrazine (200 g, crude) was obtained as a yellow gum. Step 3: (S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoic acid: [0185] (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 ethyl (S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoate was consumed completely. The 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 dried in vacuum to give desired (S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoic acid (130 PATENT Attorney Docket No.052687-509001WO 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: [0186] To acid (70.00 g, 251.32 mmol, 1 eq) in THF (750 mL) and NaOH (1 N, 750 mL) was added Boc2O (109.70 g, 502.64 mmol, 115.47 mL, 2 eq) at 0 °C, the mixture was stirred at 20 °C for 12 h. 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 organic layer was washed with water (2 L) and brine (2 L), dried over Na2SO4, filtered, and concentrated. The mixture was suspended in PE (1 L) and stirred at 20 °C for 0.5 h. Then the mixture was filtered, and the white solid was collected and dried to dryness to give compound 2 (2S)-3-(2-bromo-5-chloro-phenyl)-2-(tert-butoxycarbonylamino)propanoic acid (124 g, 320.9 mmol, 64 % yield, 98% purity) as a white solid.1H NMR: ET53616-98-P1Z (400 MHz, MeOD) δ 7.54 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.17-7.15 (m, 1H), 4.49 (dd, J = 4.4, 10.4 Hz, 1H), 3.39 (br dd, J = 4.4, 9.6 Hz, 1H), 2.94 - 2.88 (m, 1H), 1.36 - 1.28 (m, 9H). LCMS (ESI+): m/z 277.9 / 279.9 (M+H+) Step 5: Int.4: [0187] To a - - butoxycarbonylamino)propanoic acid (3.00 g x 10, 7.92 mmol, 1 eq) in THF (90 mL x 10) was added NaH (1.58 g x 10, 39.61 mmol, 60% purity, 5 eq) at 0 °C, the mixture was stirred at 0 °C for 0.5 h. Then MeI (11.25 g x 10, 79.23 mmol, 4.93 mL, 10 eq) was added at 0 °C, the mixture was stirred at 15 °C for 12 h. The LCMS showed that the (2S)-3-(2-bromo-5- PATENT Attorney Docket No.052687-509001WO chloro-phenyl)-2-(tert-butoxycarbonylamino)propanoic acid was consumed completely, and the desired product was detected. The mixture was quenched by sat. Citric acid (1.5 L), extracted with EtOAc (1.5 Lx2). The organic layer was washed with brine (1.5 L), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, PE/EtOAc/THF=20/1/0 to 6/1/1) to give crude product. The mixture was combined with ET53616-100,104. The residue was dissolved in DCM (1 L) and concentrated under reduced pressure to give the desired product Int.4 (114.0 g, 285.70 mmol, 98 % purity) as a yellow solid.1H NMR: ET53616-105-P1Z2 (400 MHz, CHLOROFORM-d) δ 11.44 (brs, 1H), 7.50 - 7.47 (m, 1H), 7.20 - 7.19 (m, 1H), 7.13 - 7.11 (m, 1H), 4.83 - 4.71 (m, 1H), 3.48- 3.43 (m, 1H), 3.31 - 3.06 (m, 1H), 2.81 - 2.70 (m, 3H), 1.44 - 1.37 (m, 9H). LCMS (ESI+): m/z 291.9/293.9 (M+H+). Int.7: Preparation of (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2- cyclopropoxypyridin-3-yl)propanoic acid Step 1: 3-Bromo-5-chloro- [0188] Into a 2-fluoropyridine (50 g, 237.61 mmol, 1 eq) in DMF (400 mL), Cs2CO3 (232.97 g, 712.83 mmol, 3 eq) was added at rt under nitrogen atmosphere. The mixture was stirred at rt for 50 min. cyclopropanol (9.94 g, 171.08 mmol, 1.2 eq) was added dropwise over 2 min at rt. The resulting mixture was stirred at 80 °C for 16 h. The reaction was quenched with ice-water (700 mL) and extracted with EA (3 x 100 mL). The organic layer combined and washed with brine (300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (0~20%).This resulted in 3-bromo-5-chloro-2-cyclopropoxypyridine (40 g, 68 %) as a colorless oil. LCMS (ESI+): m/z 249.95.1H NMR (400 MHz, DMSO-d6) δ PATENT Attorney Docket No.052687-509001WO 0.76 (ddd, J = 5.7, 4.5, 3.1 Hz, 2H) ,0.96 – 0.78 (m, 2H), 4.32 (tt, J = 6.4, 3.1 Hz, 1H), 8.17 (d, J = 2.5 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H). Step 2: Methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-cyclopropoxypyridin- 3-yl)propanoate: [0189] was added 1,2-dibromoethane (6.80 g, 36.22 mmol, 0.15 eq) in one portion under N2. Then chlorotrimethylsilane (2.62 g, 24.15 mmol, 0.1 eq) was added slowly and the mixture was stirred for 30 min at 25 oC. A solution of methyl 2-[(tert-butoxycarbonyl)amino]-3- iodopropanoate (95.36 g, 289.74 mmol, 1.2 eq) in DMA (135mL) was added dropwise slowly (60 min) to maintain temperature below 50 oC, the resulting mixture was stirred at rt for 2 h and then added 1000 mL 3-necked round-bottom flask a cannula to a solution of 3- bromo-5-chloro-2-cyclopropoxypyridine (60 g, 241.45 mmol, 1 eq), Pd(dppf)Cl2.CH2Cl2 (19.67 g, 24.14 mmol, 0.1 eq) and CuI (9.20 g, 48.29 mmol, 0.2 eq) in DMA (135 ml) under N2, the color of the mixture turned brown, then the mixture was heated and stirred at 80 oC for 2 h under N2. The mixture was quenched with ice-water (700 ml) and extracted with EA (3 x 500 ml). The organic layer was combined and washed with brine (300 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum to give the crude product. The crude product was purified by silica gel chromatography eluted with PE/EA (0~50%) to afford methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-cyclopropoxypyridin-3- yl)propanoate (30 g, 34 %) as a white solid. LCMS (ESI+): m/z 371.10. Step 3: Methyl (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(5-chloro-2- cyclopropoxypyridin-3-yl)propanoate: PATENT Attorney Docket No.052687-509001WO [0190] Into a 1000 mL round-bottom flask were added methyl (2S)-2-[(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 nitrogen atmosphere. The mixture was stirred at 0 °C for 30 min, CH3I (95.69 g, 674.16 mmol, 10 eq) was added dropwise over 2 min at 0 °C. The resulting mixture was stirred at rt for 16 h. The reaction was quenched with ice-water (500 mL) and extracted with EtOAc (3 x 500 mL). The organic layer was combined and washed with brine (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:1) to afford methyl (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(5-chloro-2- cyclopropoxypyridin-3-yl)propanoate (22 g, 85 %) as a colorless oil. LCMS (ESI+): m/z 385.10.1H NMR (400 MHz, DMSO-d6) δ 0.83 – 0.62(m, 2H), 1.19 (t, J = 7.1 Hz, 2H), 1.28 (s, 9H), 2.65 (d, J = 3.3 Hz, 3H), 2.95 (dd, J = 13.6, 10.4 Hz, 1H), 3.07(ddd, J = 14.2, 4.9, 1.9 Hz, 2H), 3.73 – 3.61 (m, 3H), 4.69 (dd, J = 10.5, 4.6 Hz, 1H), 8.12 (dd, J = 17.7, 2.6 Hz, 2H). Step 4: Int.7: N N O O NaOH Cl [0191] Into - butoxycarbonyl)(methyl)amino]-3-(5-chloro-2-cyclopropoxypyridin-3-yl)propanoate (20 g, 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 solvent was removed by reduce pressure and the residue was purified by reverse flash chromatography with the following conditions: column, C18; mobile phase, ACN in water (0.5% FA), 0% to 100% gradient in 40 min; detector, UV 254 nm. This resulted in Int.7 (13.95 g, 72%) as a yellow oil. LCMS (ESI+): m/z 371.00.1H NMR (400 MHz, DMSO-d6) δ 0.79 – 0.61 (m, 4H), 1.21 (s, 9H), 2.95 – 2.84 (m, 2H), 3.00 (s, 3H), 3.09 – 3.01 (m, 1H), 4.86 (dd, J = 11.3, 4.6 Hz, 1H), 7.67 (d, J = 2.6 Hz, 1H), 8.11 (dd, J = 18.4, 2.6 Hz, 1H). Int.13: (S)-3-(2-bromo-5-fluorophenyl)-2-((tert- butoxycarbonyl)(methyl)amino)propanoic acid: PATENT Attorney Docket No.052687-509001WO [0192] This material was procedure for Int.4 acid using 1- bromo-2-(bromomethyl)-4-fluorobenzene as the starting material. LCMS (ESI+): m/z: 376.1. Int.15: Preparation of (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2-(1- methyl-1H-pyrazol-4-yl)pyridine-3-yl)propanoic acid Step 1: 5-chloro-2-(1-methyl- 3-amine: [0193] 1 eq) and 1- methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (36.11 g, 173.53 mmol, 1.2 eq) in dioxane (720 mL) and H2O (120 mL) was added K2CO3 (39.97 g, 289.22 mmol, 2 eq) and Pd(dppf)Cl2 (3.17 g, 4.34 mmol, 0.03 eq), the mixture was stirred at 90 °C for 12 h under N2. The reaction was monitored by LCMS, which showed 2-bromo-5-chloropyridin-3- amine was consumed and one of peak with desired mass was detected. The reaction mixture was filtered, and the filter cake was washed with EtOAc (50 mL x 3) and diluted with water (10 mL), extracted with EtOAc (200 mL x 3). The combined organics were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was dissolved in DCM (80 mL), and 40 g of silica gel was added. The resulting mixture was evaporated under reduced pressure to give a dry flowing solid, and then it was loaded to Biotage® using a 180 g Agela flash silica gel column, eluted with 0 % to 40 % EtOAc in PE with the flower rate of 75 mL/min. The product fraction was combined and PATENT Attorney Docket No.052687-509001WO concentrated to give 5-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridine-3-amine (30 g, 142.35 mmol, 98 % yield, 99% purity) as a brown solid. Step 2: 5-chloro-3-iodo-2-(1-methyl-1H-pyrazol-4-yl)pyridine: [0194] (9 g, 43.14 mmol, 1 eq) in MeCN (300 mL) was added CuI (9.86 g, 51.76 mmol, 1.2 eq), KI (35.80 g, 215.68 mmol, 5 eq) and tert-butyl nitrite (22.24 g, 215.68 mmol, 25.65 mL, 5 eq), the mixture was stirred at 60 °C for 12 h under N2. The reaction was monitored by LCMS, which showed 5-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridine-3-amine was consumed and one of peak with desired mass was detected. After cooling to rt, the solid was collected by filtration, washed with EtOAc (100 mL x 3) and dried under reduced pressure to give a brown solid. The solid was triturated with EtOAc at 20 oC for 30 min. Then the crude product was triturated with ammonia water at 20 oC for 30 min and filtered, the filter cake was concentrated to give 5- chloro-3-iodo-2-(1-methyl-1H-pyrazol-4-yl)pyridine (20.5 g, 50.04 mmol, 58 % yield, 78% purity) brown solid. Step 3: Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazol- 4-yl)pyridine-3-yl)propanoate: [0195] (20.5 g, 64.16 mmol, 1 eq) in DMF (200 mL) was added (R)-(2-((tert-butoxycarbonyl)amino)-3- methoxy-3-oxopropyl)zinc(II) iodide (50.62 g, 128.31 mmol, 2 eq), Pd2(dba)3 (2.94 g, 3.21 mmol, 0.05 eq) and sPhos (2.63 g, 6.42 mmol, 0.1 eq), the mixture was stirred at 20 °C for 12 h under N2. The reaction was monitored by LCMS, which showed 5-chloro-3-iodo-2-(1- methyl-1H-pyrazol-4-yl)pyridine was consumed and one of peak with desired mass was detected. The reaction was quenched by addition of saturated ammonium chloride aqueous PATENT Attorney Docket No.052687-509001WO solution (200 mL) and extracted with EtOAc (100 mL x 3). The combined organics were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was dissolved in DCM (50 mL), and 40 g of silica gel was added. The resulting mixture was evaporated under reduced pressure to give a dry flowing solid, and then it was loaded to Biotage® using a 120 g Agela flash silica gel column, eluted with 0 % to 55 % EtOAc in PE with the flower rate of 75 mL/min. The product fraction was combined and concentrated to give methyl (S)-2-((tert- butoxycarbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl)propanoate (8 g, 19.86 mmol, 31 % yield, 98% purity) as a yellow solid. Step 4: (S)-2-((tertbutoxycarbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazol-4- yl)pyridine-3-yl)propanoic acid: [0196] (1- methyl-1H-pyrazol-4-yl)pyridine-3-yl)propanoate (8 g, 20.26 mmol, 1 eq) in THF (100 mL) was added a solution of LiOH.H2O (1.02 g, 24.31 mmol, 1.2 eq) in H2O (50 mL), the mixture was stirred at 20 °C for 1 h. The reaction was monitored by LCMS, which showed methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridine-3- yl)propanoate was consumed and one of peak with desired mass was detected. The mixture was extracted with EtOAc (100 mL). The aqueous phase was acidified by added hydrochloric acid (1 M, 50 mL) dropwise at 0 °C to pH = 4 and extracted with EtOAc (200 mL x 3). The combined organics were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give (S)-2-((tertbutoxycarbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazol- 4-yl)pyridine-3-yl)propanoic acid (7 g, 18.01 mmol, 89 % yield, 98% purity) as a yellow solid. Step 5: Int.15: PATENT Attorney Docket No.052687-509001WO N N N N N N Cl 1H- pyrazol-4-yl)pyridine-3-yl)propanoic acid (3.7 g, 9.72 mmol, 1 eq) in THF (100 mL) was added NaH (1.94 g, 48.58 mmol, 60% purity, 5 eq) at 0 °C, the mixture was stirred at 0 °C for 1 h under N2. MeI (13.79 g, 97.16 mmol, 6.05 mL, 10 eq) was added to the reaction mixture, the mixture was stirred at 20 °C for 12 h under N2. The reaction was monitored by LCMS, which showed (S)-2-((tertbutoxycarbonyl)amino)-3-(5-chloro-2-(1-methyl-1H- pyrazol-4-yl)pyridine-3-yl)propanoic acid was consumed and one of peak with desired mass was detected. The reaction mixture was cooled to 0 °C and quenched by NH4Cl (30 mL), extracted with EtOAc (50 mL x 2). The combined organics were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give Int.15 (3 g, 7.51 mmol, 77 % yield, 98 % purity) as a yellow solid.1H NMR (400 MHz, MeOD-d4) 1H NMR (400 MHz, METHANOL-d4) δ = 8.48 - 8.32 (m, 1H), 8.08 (d, J = 6.8 Hz, 1H), 7.92 (s, 1H), 7.76 - 7.64 (m, 1H), 4.80 - 4.66 (m, 1H), 3.98 (s, 3H), 3.64 - 3.56 (m, 1H), 3.28 - 3.16 (m, 1H), 2.66 (d, J = 9.8 Hz, 3H), 1.24 (s, 9H) Int.22: Preparation of (2S,4R)-1-(3,3-difluoro-1-(trifluoromethyl)cyclobutane-1- carbonyl)-4-fluoropyrrolidine-2-carboxylic acid Step 1: Methyl (2S,4R)-4- PATENT Attorney Docket No.052687-509001WO [0198] A solution of 1-tert-butyl 2-methyl (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (150 g, 101.1 mmol, 1 eq) and HCl(gas) in 1,4-dioxane (758.29 mL, 505.53 mmol, 5 eq) was stirred for 0.5 h at rt and then concentrated under vacuum to afford methyl (2S,4R)-4- fluoropyrrolidine-2-carboxylate (110 g, yield, 99%, purity 80%) as a white solid. The crude product was used in the next step directly without further purification. LCMS (ESI+): m/z 148.15 (M+H+). Step 2: Methyl (2S,4R)-1-[3,3-difluoro-1-(trifluoromethyl)cyclobutanecarbonyl]-4- fluoropyrrolidine-2-carboxylate: [0199] To a (110 g, 103.3 mmol, 1 eq, 80%), 3,3-difluoro-1-(trifluoromethyl)cyclobutane-1-carboxylic acid (122.06 g, 103.3 mmol, 1 eq) and TCFH (251.69 g, 154.95 mmol, 1.5 eq) in ACN (1100 mL) was added NMI (245.51 g, 516.49 mmol, 5 eq) dropwise in 45 min at 0 °C. The mixture was slowly warmed up to rt and stirred overnight at rt. The mixture was concentrated under vacuum at 28 oC 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 layers were washed with saturated NaHCO3 (1000 mL x1). The aqueous layer was extracted with EtOAc (300mL x1) again. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to afford methyl (2S,4R)-1-[3,3-difluoro-1-(trifluoromethyl)cyclobutanecarbonyl]-4- fluoropyrrolidine-2-carboxylate 180 g, 81 %) as a light-yellow solid. The crude product was used in the next step directly without further purification. LCMS (ESI+): m/z 334.15 (M+H+). Step 3: Int.22: PATENT Attorney Docket No.052687-509001WO F F F F 3 [0200] To a (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 oC. 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 oC. Then the precipitated solids were collected by filtration and washed with water (3x200 mL). The filtrate was added HCl (3N,100 mL). The precipitated solids were collected by filtration and washed with water (3x100 mL). The combined solids were dried in an oven for 16 h at 40 oC. This resulted in afford Int.22 (150.7 g, 97 %) as a white solid. LCMS (ESI+): m/z 319.95 (M+H+). Int.23: Preparation of (2S,4R)-4-fluoro-1-(1-(trifluoromethyl)cyclobutane-1- carbonyl)pyrrolidine-2-carboxylic acid: [0201] This compound was general synthetic sequence described for the preparation of Int.22 with 1-(trifluoromethyl)cyclobutane-1-carboxylic acid as the starting material. LCMS (ESI+): m/z 283.08 (M+H+). Int.24: Preparation of (2S,4R)-4-fluoro-1-((R)-2-(trifluoromethyl)tetrahydro-2H-pyran- 2-carbonyl)pyrrolidine-2-carboxylic acid PATENT Attorney Docket No.052687-509001WO Step 1: Methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate: [0202] A mixture 1,2-dicarboxylate (20 g, 80.9 mmol, 1 eq) in HCl/EtOAc (200 mL) (4 M) was stirred at 25 °C for 2 h. LC-MS showed starting material was consumed and one main peak with desired mass was detected. The reaction mixture was concentrated to give methyl (2S,4R)-4-fluoropyrrolidine-2- carboxylate (15 g, crude, HCl) as a light-yellow solid. This was taken on to the next reaction without further purification. Step 2: (2S,4R)-4-fluoro-1-((R)-2-(trifluoromethyl)tetrahydro-2H-pyran-2- carbonyl)pyrrolidine-2-carboxylate and (2S,4R)-4-fluoro-1-((S)-2- (trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate: [0203] (13 g, 65.61 mmol, 1 eq) in DCM (200 mL) was added DIEA (8.48 g, 65.61 mmol, 11.43 mL, 1 eq), and the mixture was stirred for 10 min, then BOP-Cl (18.37 g, 72.17 mmol, 1.1 eq), methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate, and DIEA (16.96 g, 131.22 mmol, 22.86 mL, 2 eq) were added. The mixture was stirred at 25 °C for 12 h. LC-MS showed one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove DCM, and then EtOAc (30 mL) was added. The solution was washed three times with 5% NaHCO3 solution (15 mL) and once consecutively with water (15 mL), 2M HCl solution (15 mL), water (15 mL) and saturated brine (15 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EtOAc = 10:1 to 2:1) to give methyl (2S,4R)-4-fluoro-1-((R)-2- (trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate (10.7 g, 31.7 PATENT Attorney Docket No.052687-509001WO mmol, 48 % yield, 96.8% purity) as a light yellow oil and to give methyl (2S,4R)-4-fluoro-1- ((S)-2-(trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate (11 g, 32.0 mmol, 49 % yield, 95.2% purity) as a light yellow oil. Step 3: (2S,4R)-4-fluoro-1-((R)-2-(trifluoromethyl)tetrahydro-2H-pyran-2- carbonyl)pyrrolidine-2-carboxylic acid: [0204] To a 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 the mixture was stirred at 25 °C for 1 hr. LC-MS showed methyl (2S,4R)-4-fluoro-1-((R)-2- (trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate was consumed and one main peak with desired mass was detected. The mixture was acidified at 0 °C with HCl (1 N) until pH = 2~3. Then the mixture was extracted with EtOAc 300 mL (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EtOAc = 10:1 to 2:1) to give Int.24 (8.9 g, 28.33 mmol, 89 % yield, 99 % purity) as a white solid. LCMS (ESI+): m/z 314.0 (M+H+). Int.17: (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2- (cyclopropylthio)pyridin-3-yl)propanoic acid Step 1: 5-chloro-3- PATENT Attorney Docket No.052687-509001WO [0205] To a solution of 5-chloro-2-fluoro-3-nitropyridine (15 g, 84.97 mmol, 1 eq) in DMF (150 mL) was added Na2S (7.96 g, 101.96 mmol, 4.28 mL, 1.2 eq) and the reaction mixture was stirred at 20 °C for 2 hrs. LCMS analysis showed starting material was consumed and the reaction mixture was quenched by the addition of water (1000 mL), acidified to pH = 4~5 with 1N HCl, and extracted with EtOAc (3 x 400 mL). The combined organics were washed with water (2 x 300 m) and brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 5-chloro-3-nitropyridine-2-thiol (12.67 g, 59.48 mmol, 58.3%) as a yellow solid, which was used into the next step without further purification. LCMS (ESI+): m/z 191.1 (M+H+).1H NMR (400 MHz, DMSO-d6): δ 8.19 – 8.20 (dd, 1H), 8.40 – 8.41 (dd, 1H), 14.68 – 14.75 (m, 1H). Step 2: 5-chloro-2-(cyclopropylthio)-3-nitropyridine: [0206] A 1 eq), cyclopropylboronic acid (34.25 g, 398.73 mmol, 2 eq), Cu(OAc)2 (72.42 g, 398.73 mmol, 2 eq) and TEA (80.69 g, 797.45 mmol, 110.99 mL, 4 eq) in DCM (400 mL) was purged with O2, and then the mixture was stirred at 20 °C for 16 hr under O2 atmosphere. Upon consumption of starting material (LCMS), the reaction mixture was quenched by the addition of water (300 mL), and extracted with DCM (200 mL x 2). The combined organics were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with MTBE (250 mL) and the heterogeneous mixture was filtered and the filtrate was concentrated under reduced pressure to give 5-chloro-2- (cyclopropylthio)-3-nitropyridine (31.8 g, 128.21 mmol, 64.31%) as a dark brown solid. LCMS (ESI+): m/z 231.1 (M+H+).1H NMR (400 MHz, DMSO-d6): δ 1.102 (m, 4H), 2.41 – 2.44 (m, 1H), 8.72– 8.73 (dd, 1H), 8.97 – 8.98 (dd, 1H). Step 3: 5-chloro-2-(cyclopropylthio)pyridin-3-amine: PATENT Attorney Docket No.052687-509001WO [0207] To a solution of 5-chloro-2-(cyclopropylthio)-3-nitropyridine (21 g, 91.04 mmol, 1 eq) in EtOH (150 mL) and H2O (150 mL) was added Fe (10.17 g, 182.08 mmol, 2 eq) and NH4Cl (9.74 g, 182.08 mmol, 2 eq). The mixture was stirred at 80 °C for 1 hr. LCMS indicated that the starting material was consumed completely. The reaction mixture was cooled to room temperature, filtered, then quenched by water (100 mL), concentrated under reduced pressure to remove EtOH, extracted with EtOAc (200 mL x 2). The combined organics were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 5-chloro-2-(cyclopropylthio)pyridin-3-amine (14.4 g, 68.38 mmol, 75.11%) as a dark brown solid, which was used into the next step without further purification. LCMS (ESI+): m/z 201.1 (M+H+).1H NMR (400 MHz, DMSO-d6): δ 0.52 – 0.56 (m, 2H), 0.97 – 1.02 (m, 2H), 2.34 – 2.39 (m, 1H), 6.95 – 6.96 (dd, 1H), 7.76 – 7.77 (dd, 1H).’ Step 4: 5-chloro-2-(cyclopropylthio)-3-iodopyridine: [0208] To a g, 49.83 mmol, 1 eq) in HCl (3 M, 83.05 mL, 5 eq) and MeCN (100 mL) was added a solution of NaNO2 (3.78 g, 54.81 mmol, 1.1 eq) in H2O (50 mL) slowly at 0 °C. The mixture was stirred at 20 °C for 0.5 hr. Then a solution of KI (16.54 g, 99.66 mmol, 2 eq) in H2O (100 mL) was added slowly and the reaction mixture was stirred at 20 °C for 12 hr. LCMS indicated that the starting material was consumed completely, and the aqueous phase was separated and basified with Na2CO3 to pH = 7~8. The mixture was extracted with EtOAc (2 × 100 mL), and the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, EtOAc in Pet. ether 0-5%) to give 5-chloro-2-(cyclopropylthio)-3-iodopyridine (7.1 g, 20.24 mmol, 40.61%) as a dark brown oil. LCMS (ESI+): m/z 311.9 (M+H+).1H NMR (400 MHz, DMSO-d6): δ 0.57 – 0.61 (m, 2H), 1.05 – 1.09 (m, 2H), 2.30 – 2.34 (m, 1H), 8.29 – 8.30 (dd, 1H), 8.57 – 8.58 (dd, 1H). Step 5: methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2- (cyclopropylthio)pyridin-3-yl)propanoate: PATENT Attorney Docket No.052687-509001WO [0209] A degassed and purged with N2. Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (16 g, 48.61 mmol, 1 eq) in DMF (40 mL) was added dropwise, I2 (3.70 g, 14.58 mmol, 2.94 mL, 0.3 eq) in DMF (20 mL) was then added dropwise. The reaction mixture was stirred at 20 °C for 1 hr. The resulting zincate solution was used into the next step. [0210] To a solution of 5-chloro-2-(cyclopropylthio)-3-iodopyridine (7 g, 22.47 mmol, 1 eq) in DMF (50 mL) was added SPhos (922.33 mg, 2.25 mmol, 0.1 eq) and Pd2(dba)3 (1.03 g, 1.12 mmol, 0.05 eq) under N2 atmosphere. The zincate prepared above (47.18 mmol, 2.1 eq) was added and the reaction mixture was stirred at 65 °C for 12 hr under N2 atmosphere. LCMS indicated that the starting material was consumed completely. The reaction mixture was cooled to room temperature and quenched by the addition of water (200 mL), extracted with EtOAc (150 mL x 2). The combined organic layer were washed with water (150 mL x 2) and brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by RP-HPLC (MeCN in Water +0.1% TFA 40-70%). Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-(cyclopropylthio)pyridin-3-yl)propanoate (3.5 g, 8.69 mmol, 38.69%) was isolated as a light yellow solid. LCMS (ESI+): m/z 387.1 (M+H+).1H NMR (400 MHz, DMSO-d6): δ 0.56 – 0.60 (m, 2H), 1.05 – 1.07 (m, 2H), 1.30(s, 9H), 2.38 – 2.41 (m, 1H), 2.79 – 2.99 (m, 2H), 3.65 (s, 1H), 4.29 – 4.35 (m, 1H), 7.33 – 7.35 (d, 1H), 7.60 – 7.61 (dd, 1H), 8.44 – 8.45 (dd, 1H). Step 6: (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-(cyclopropylthio)pyridin-3- yl)propanoic acid: PATENT Attorney Docket No.052687-509001WO [0211] To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2- (cyclopropylthio)pyridin-3-yl)propanoate (0.8 g, 2.07 mmol, 1 eq) in THF (20 mL) and H2O (20 mL) was added LiOH•H2O (173.54 mg, 4.14 mmol, 2 eq) and the reaction mixture was stirred at 20 °C for 0.5 hr. Upon the consumption of starting material (LCMS), the reaction mixture was concentrated under reduced pressure to remove THF, and 1N HCl was added to adjust the pH to ~3. The aqueous layer was extracted with EtOAc (20 mL x 2). The combined organics were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2- (cyclopropylthio)pyridin-3-yl)propanoic acid (725 mg, 1.86 mmol, 90.0%) as a light yellow solid, which was used in the next step without further purification. LCMS (ESI+): m/z 373.1 (M+H+).1H NMR (400 MHz, DMSO-d6): δ 0.56 – 0.60 (m, 2H), 1.05 – 1.07 (m, 2H), 1.30 (s, 9H), 2.38 – 2.40 (m, 1H), 2.75 – 2.78(m, 1H), 2.99 – 3.33 (m, 1H), 4.20 – 4.25 (m, 1H), 7.18 – 7.20 (d, 1H), 7.59 – 7.60 (dd, 1H), 8.43 – 8.44 (dd, 1H), 12.79 (s, 1H). Step 7: Int.4: O O H O N O N Cl [0212] (cyclopropylthio)pyridin-3-yl)propanoic acid (1.44 g, 3.86 mmol, 1 eq) in THF (30 mL) was added 60% NaH (463.39 mg, 11.59 mmol, 3 eq) at 0 °C under N2. The mixture was stirred at ambient temperature for 0.5 hr. Then, MeI (5.48 g, 38.62 mmol, 2.40 mL, 10 eq) was added and the reaction mixture was stirred at 25 °C for 12 hrs. Upon the consumption of starting material (LCMS), the reaction mixture was quenched with the addition of ice-water (~60 mL), concentrated under reduced pressure to remove THF. The basic aqueous phase was extracted with pet. ether (40 mL x 2) then, the aqueous phase was slowly acidified to pH ~3 with 1N HCl. The acidic aqueous phase was then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give Int.4 (1.42g, 3.68 mmol, 95.3%). LCMS (ESI+): m/z 387.0 (M+H+). 1H NMR (400 MHz, DMSO-d6): δ 13.04 (d, J = 1.5 Hz, 1H), 8.50 - 8.37 (m, 1H), 7.64 - 7.46 (m, 1H), 4.90 - 4.66 (m, 1H), 3.11 - 2.91 (m, 2H), 2.65 (s, 3H), 2.39 (dt, J = 3.8, 7.8 Hz, 1H), 1.30 - 1.17 (m, 9H), 1.07 (d, J = 5.5 Hz, 2H), 0.57 (s, 2H). PATENT Attorney Docket No.052687-509001WO Int.21: (2S,6S)-2,6-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)morpholine Step 1: (2S,6S)-4-(4- [0213] eq) in DCM (45 mL) was added (2S,6S)-2,6-dimethylmorpholine (2.8 g, 24.31 mmol, 1 eq), TEA (4.92 g, 48.62 mmol, 6.77 mL, 2 eq) and Cu(OAc)2 (883.15 mg, 4.86 mmol, 0.2 eq) under O2 atmosphere, and the mixture was stirred at 25 °C for ~6 hr. Upon consumption of starting material (LCMS), the reaction mixture was filtered, and the filter cake was washed with DCM (6 x 20 mL). To the filtrate was added saturated NH4Cl (30 mL). The aqueous layer was extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 – 3 % EtOAc in pet. ether). (2S,6S)-4-(4-bromophenyl)-2,6-dimethylmorpholine (3 g, 8.22 mmol, 33.80%) was obtained as a white solid. LCMS (ESI+): m/z 270.1 (M+H+).1H NMR (400 MHz, CDCl3-d): δ 7.35 (d, J = 9.2, 11.6 Hz, 2H), 6.78 (d, J = 9.0 Hz, 2H), 4.24 - 4.10 (m, 2H), 3.18 (dd, J = 3.3, 11.6 Hz, 2H), 2.90 - 2.82 (m, 2H), 1.32 (d, J = 6.5 Hz, 6H) Step 2: Int.21: PATENT Attorney Docket No.052687-509001WO mmol, 1 eq) in dioxane (30 mL) was added B2Pin2 (4.23 g, 16.66 mmol, 1.5 eq) and KOAc (2.18 g, 22.21 mmol, 2 eq) under N2 atmosphere. The suspension was degassed and purged with N2, then Pd(dppf)Cl2 (812.51 mg, 1.11 mmol, 0.1 eq) was added. The mixture was stirred at 80 °C for 12hr. Upon consumption of starting material (LCMS), the reaction was cooled, filtered, and the filter cake was rinsed with EtOAc (3 x 20 mL). The filtrate was concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 – 3 % EtOAc in Pet. ether). Int.21 (1.55 g, 4.79 mmol, 43.14%) was obtained as a pale yellow solid. LCMS (ESI+): m/z 318.2 (M+H+).1H NMR (400 MHz, DMSO-d6): δ 7.72 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 4.22 - 4.10 (m, 2H), 3.30 (dd, J = 3.3, 12.0 Hz, 2H), 2.98 (dd, J = 6.3, 12.0 Hz, 2H), 1.34 (s, 12H), 1.32 (s, 3H), 1.30 (s, 3H). Int.25: Preparation of (S)-2-(2-((2S,4R)-1-(3,3-difluoro-1-(trifluoromethyl)cyclobutane- 1-carbonyl)-4-fluoropyrrolidin-2-yl)-4-oxo-3,4-dihydro-5H-imidazo[4,5-c]pyridin-5- yl)pent-4-enoic acid: Step 1: Tert-butyl (3- oxo- carbamate: PATENT Attorney Docket No.052687-509001WO [0215] To a stirred solution of 4-amino-3-nitro-1H-pyridin-2-one (5 g, 19.341 mmol, 1 equiv), DMAP (236.29 mg, 1.934 mmol, 0.1 equiv) and TEA (8.87 g, 58.023 mmol, 3 equiv) in DMF (50 mL) was added Boc2O (6.22 g, 19.341 mmol, 1 equiv) at 25 °C. The resulting mixture was stirred for 16hr at 25 °C. The reaction solution was directly purified by reverse phase flash (0-50% MeCN in water with 0.1% TFA) to afford tert-butyl N-(3-nitro-2-oxo- 1H-pyridin-4-yl)carbamate (5 g, 60.77%) as a yellow oil. LCMS (ESI+): m/z 256.05 (M+H+). Step 2: Methyl (S)-2-(4-((tert-butoxycarbonyl)amino)-3-nitro-2-oxopyridin-1(2H)- yl)pent-4-enoate: [0216] To (5 g, 19.590 mmol, 1 equiv) in DMF (80 mL) was added 60% NaH (1175.31 mg, 29.385 mmol, 1.5 equiv) in portions at 0°C. The resulting mixture was stirred for 10 min at 0°C. To this mixture was added methyl methyl (2S)-2-(trifluoromethanesulfonyloxy)pent-4-enoate (5.14 g, 19.590 mmol, 1 equiv)in DMF (10 mL) at 0 °C. The resulting mixture was stirred for 16h at 25 °C. The reaction was quenched with ice water at 0°C and extracted with EtOAc (3 x 120mL). The combined organic layers were washed with brine (120 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give methyl (2S)-2-{4-[(tert-butoxycarbonyl)amino]-3-nitro-2-oxopyridin-1-yl}pent-4-enoate (5 g, 59.06%) as a yellow. This product was used in the next step directly without any further purification. LCMS (ESI+): m/z 368.1 (M+H+). Step 3: Methyl (S)-2-(3-amino-4-((tert-butoxycarbonyl)amino)-2-oxopyridin-1(2H)- yl)pent-4-enoate: PATENT Attorney Docket No.052687-509001WO [0217] To a stirred mixture of methyl (2S)-2-{4-[(tert-butoxycarbonyl)amino]-3-nitro-2- oxopyridin-1-yl}pent-4-enoate (5 g, 13.611 mmol, 1 equiv) and Zn powder (13.35 g, 204.165 mmol, 15 equiv) in EtOH (500 mL) was added NH4Cl (10.92 g, 204.165 mmol, 15 equiv) in H2O (50 mL). The solution was added slowly at 0°C. The resulting mixture was stirred for 3 hr at 60°C. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3x10 mL). The filtrate was concentrated under reduced pressure to remove EtOH. The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with H2O (3x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford methyl (2S)-2-{3-amino-4-[(tert- butoxycarbonyl)amino]-2-oxopyridin-1-yl}pent-4-enoate (4.5 g, 98.00%) as a yellow oil. LCMS (ESI+): m/z 338.15 (M+H+). Step 4: Methyl (S)-2-(4-((tert-butoxycarbonyl)amino)-3-((2S,4R)-1-(3,3-difluoro-1- (trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxamido)-2- oxopyridin-1(2H)-yl)pent-4-enoate: - -2- oxopyridin-1-yl}pent-4-enoate (3.27 g, 9.692 mmol, 1 equiv), (2S,4R)-1-[3,3-difluoro-1- (trifluoromethyl)cyclobutanecarbonyl]-4-fluoropyrrolidine-2-carboxylic acid (3.09 g, 9.692 mmol, 1 equiv) and TCFH ( 4.07g, 14.538mmol, 1.5eq) in MeCN (80 mL) was added NMI (2.39 g, 29.076 mmol, 3 equiv) dropwise at 0°C under an atmosphere of N2. The resulting mixture was warmed to ambient temperature and stirred until the consumption of starting material (LCMS). The resulting mixture was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography (C18, 10-50% MeCN in water with 0.1% FA). This resulted in methyl (2S)-2-{4-[(tert-butoxycarbonyl)amino]-3-[(2S,4R)- 1-[3,3-difluoro-1-(trifluoromethyl)cyclobutanecarbonyl]-4-fluoropyrrolidine-2-amido]-2- PATENT Attorney Docket No.052687-509001WO oxopyridin-1-yl}pent-4-enoate (6 g, 96.94%) as a yellow solid. LCMS (ESI+): m/z 639.15 (M+H+). Step 5: Methyl (S)-2-(2-((2S,4R)-1-(3,3-difluoro-1-(trifluoromethyl)cyclobutane-1- carbonyl)-4-fluoropyrrolidin-2-yl)-4-oxo-3,4-dihydro-5H-imidazo[4,5-c]pyridin-5- yl)pent-4-enoate: F F F [3,3- difluoro-1-(trifluoromethyl)cyclobutanecarbonyl]-4-fluoropyrrolidine-2-amido]-2- oxopyridin-1-yl}pent-4-enoate (2 g, 3.132 mmol, 1 equiv) in AcOH (10 mL, 174.515 mmol, 55.72 equiv) was stirred for 16 hr at 120°C. The resulting mixture was concentrated under reduced pressure to give crude product (2.0g) which was used in the next step directly without further purification. LCMS (ESI+): m/z 521.30 (M+H+). Step 6: Int.25: - - (trifluoromethyl)cyclobutanecarbonyl]-4-fluoropyrrolidin-2-yl]-4-oxo-3H-imidazo[4,5- c]pyridin-5-yl}pent-4-enoate (5 g, 9.607 mmol, 1 equiv) in THF (50 mL) was added NaOH (7.69 g, 192.140 mmol, 20 equiv) in H2O (50mL) dropwise at 0°C over 20 min. The resulting mixture was stirred for 5hr at 20 °C. Then, the reaction was concentrated under reduced pressure and acidified to pH=3 with 1N HCl. The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with H2O (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced PATENT Attorney Docket No.052687-509001WO pressure. The residue was purified by prep-HPLC (C18, 10-50% MeCN in water with 0.1% TFA. (2S)-2-{2-[(2S,4R)-1-[3,3-difluoro-1-(trifluoromethyl)cyclobutanecarbonyl]-4- fluoropyrrolidin-2-yl]-4-oxo-3H-imidazo[4,5-c]pyridin-5-yl}pent-4-enoic acid (1.96 g, 40.25%) was isolated as a white solid. LCMS (ESI+): m/z 507.0 (M+H+).1H NMR (400 MHz, DMSO-d6) δ: 2.14 – 2.41 (m, 1H), 2.57 – 2.93 (m, 3H), 3.21 (dd, J = 37.4, 15.0 Hz, 3H), 3.54 – 4.14 (m, 3H), 4.72 – 5.78 (m, 6H), 6.53 (dd, J = 19.1, 7.3 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 12.71 (d, J = 331.8 Hz, 2H). Int.27: (S)-2-(3-((tert-butoxycarbonyl)amino)-5-methyl-2-oxopyridin-1(2H)-yl)pent-4- enoic acid Step 1: tert-butyl (5-methyl-2- 3-yl)carbamate: [0221] To a mmol, 1 eq) in THF (350 mL) was added Boc2O (80.87 g, 370.55 mmol, 85.13 mL, 2 eq). The mixture was stirred at 70 °C for 12hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO20-10% EtOAc in pet. ether). Tert-butyl (5-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamate (35.5 g, 144.05 mmol, 77.75%) was obtained as a yellow solid. LCMS (ESI+): m/z 225.2 (M+H+).1H NMR (400 MHz, CDCl3-d6): δ 12.62 - 11.95 (m, 1H), 8.02 (s, 1H), 7.55 (s, 1H), 6.79 (s, 1H), 2.12 (s, 3H), 1.53 (s, 9H). Step 2: methyl (S)-2-(3-((tert-butoxycarbonyl)amino)-5-methyl-2-oxopyridin-1(2H)- yl)pent-4-enoate: PATENT Attorney Docket No.052687-509001WO [0222] Step of Int.26 step 2. LCMS (ESI+): m/z 337.1 (M+H+).1H NMR (400 MHz, CDCl3-d6): δ 7.88 (s, 1H), 7.63 (s, 1H), 6.68 (s, 1H), 5.65 (td, 1H), 5.42 (dd, 1H), 5.14 - 5.00 (m, 2H), 3.75 (s, 3H), 3.03 - 2.88 (m, 1H), 2.74 (td, 1H), 2.10 (s, 3H), 1.50 (s, 9H). Step 3: Int.27: [0223] 2- oxopyridin-1(2H)-yl)pent-4-enoate (5 g, 14.86 mmol, 1 eq) in EtOAc (75 mL) was added MgI2 (8.27 g, 29.73 mmol, 1.87 mL, 2 eq) .The mixture was stirred at 40 °C for 2h. Upon consumption of starting material (LCMS), the reaction mixture was diluted with H2O (2 x 60 mL). Then, 1N HCl (10 mL) was used to adjust the pH to 2~3.The acidified water layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Int.27 (3.51g, 10.8 mmol, 72%) was obtained as a pink solid. LCMS (ESI+): m/z 323.2 (M+H+).1H NMR (400 MHz, CDCl3-d): δ 9.16 - 8.70 (s, 1H), 7.98 (s, 1H), 7.64 (s, 1H), 6.71 (s, 1H), 5.73 - 5.56 (m, 1H), 5.34 - 5.21 (m, 1H), 5.15 - 5.01 (m, 2H), 3.08 - 2.93 (m, 1H), 2.90 - 2.76 (m, 1H), 2.12 (s, 3H), 1.51 (s, 9H). Int.28: Preparation of (S)-2-(3-((tert-butoxycarbonyl)amino)-6-methyl-2-oxopyridin- 1(2H)-yl)pent-4-enoic acid: PATENT Attorney Docket No.052687-509001WO Step 1: tert-butyl (6-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamate: [0224] To a stirred (5 g, 32.651 mmol, 1 equiv) and TEA (6.61 g, 65.302 mmol, 2 equiv) in 2-methylpropan-2-ol (60 mL) was added DPPA (13.48 g, 48.977 mmol, 1.5 equiv) at 20 °C. The resulting mixture was stirred for 16hr at 90 °C. The resulting mixture was diluted with H2O (100mL) and was extracted with EtOAc (3 x 100mL). The combined organic layers were washed with H2O (3 x 100mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (SiO2, 50% EtOAc in ethyl ether) to afford tert-butyl N-(6-methyl-2-oxo-1H-pyridin-3-yl)carbamate (3.3 g, 45.07%) as a white solid. LCMS (ESI+): m/z 225.0 (M+H+). Step 2: methyl (S)-2-(3-((tert-butoxycarbonyl)amino)-6-methyl-2-oxopyridin-1(2H)- yl)pent-4-enoate: [0225] A solution of (2.5 g, 11.148 mmol, 1 equiv) in THF (30mL) was treated with 60% NaH (579.64 mg, 14.492 mmol, 1.30 equiv) at 0 °C. The reaction was stirred for 1 hr and methyl (2R)-2- (trifluoromethanesulfonyloxy)pent-4-enoate (2.92 g, 11.148 mmol, 1 equiv). The reaction was warmed to ambient temperature and stirred for 16 hr. The reaction was quenched with H2O (100 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure to remove THF, and the resulting mixture was diluted with H2O (30mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with H2O (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography (C18, 10-50% MeCN in water with 0.1%FA) to afford methyl (2S)-2-{3-[(tert-butoxycarbonyl)amino]-6-methyl-2- PATENT Attorney Docket No.052687-509001WO oxopyridin-1-yl}pent-4-enoate (2g, 53.33%) as a white solid. LCMS (ESI+): m/z 337.4 (M+H+). Step 3: Int.28: [0226] To methyl 1- yl}pent-4-enoate (1.8 g, 5.351 mmol, 1 equiv) in THF (10 mL) was added LiOH (0.38 g, 16.053 mmol, 3 equiv) in H2O (10 mL). The resulting mixture was stirred for 1hr at ambient temperature. Upon consumption of starting material (LCMS), the reaction mixture was acidified to ~pH 3 with 1N HCl and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product. The ee of the product was increased from ~50% to 98% via SFC (Lux 5 μm Cellulose-43 x 25 cm, 5 μm; 43% MeOH in CO2; RT1(min): 2.2; RT2(min): 3.4). Int.28 (0.73 g, 39.87%) was isolated as a brown solid. LCMS (ESI+): m/z 323.4 (M+H+).1H NMR (400 MHz, DMSO- d6) δ 7.65 (d, J = 6.3 Hz, 2H), 5.92 (d, J = 125.5 Hz, 2H), 5.65 (s, 1H), 4.96 – 4.63 (m, 3H), 2.90 (t, J = 15.1 Hz, 2H), 2.26 (s, 3H), 1.45 (s, 9H). Int.29: Preparation of(S)-2-(3-((tert-butoxycarbonyl)amino)-5-chloro-2-oxopyridin- 1(2H)-yl)pent-4-enoic acid: Step 1: tert-butyl (5-chloro-2-oxo- 3-yl)carbamate: [0227] To a stirred solution 3-amino-5-chloro-1H-pyridin-2-one (4 g, 27.670 mmol, 1 equiv) and Boc2O (6.64 g, 30.437 mmol, 1.1 equiv) in THF (80 mL) were added TEA (8.40 PATENT Attorney Docket No.052687-509001WO g, 83.010 mmol, 3 equiv) and DMAP (0.34 g, 2.767 mmol, 0.1 equiv) at ambient temperature. The resulting mixture was stirred overnight. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (SiO2¸ 5% MeOH in DCM) to afford tert-butyl N-(5-chloro-2-oxo-1H- pyridin-3-yl)carbamate (3 g, 44.31%) as a white solid. LCMS (ESI+): m/z 245.1 (M+H+). Step 2: methyl (S)-2-(3-((tert-butoxycarbonyl)amino)-5-chloro-2-oxopyridin-1(2H)- yl)pent-4-enoate [0228] To a (2 g, 8.174 mmol, 1.00 equiv) in THF (80 mL) was added 60% NaH (0.43 g, 10.626 mmol, 1.3 equiv) at 0°C. The resulting mixture was stirred for 1hr at room temperature under N2. Methyl (2R)-2-(trifluoromethanesulfonyloxy)pent-4-enoate (2.14 g, 8.174 mmol, 1 equiv) in THF (80 mL) was then slowly added. The resulting mixture was warmed to ambient temperature and stirred overnight. The mixture was quenched with water (25 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4. Filtered, and concentrated. The crude residue was purified by RP flash chromatography (C18, 10-10% MeCN in water with 0.1% FA) to afford (2S)-2-{3-[(tert-butoxycarbonyl)amino]-5-chloro-2-oxopyridin-1-yl}pent-4-enoic acid (1.8g, 5.04 mmol, 61%). LCMS (ESI+): m/z 357.2 (M+H+). Step 3: Int.29: [0229] To a stirred solution of methyl (2S)-2-{3-[(tert-butoxycarbonyl)amino]-5-chloro-2- oxopyridin-1-yl}pent-4-enoate (0.8 g, 2.242 mmol, 1 equiv) in THF (10 mL) was added LiOH (0.27 g, 11.210 mmol, 5 equiv) in H2O (10 mL) at room temperature. The PATENT Attorney Docket No.052687-509001WO resulting mixture was stirred for 30 min. Upon consumption of starting material (monitored by LCMS), the mixture was acidified to pH ~4 with 1N HCl. The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product. The ee of the product was increased from ~50% to 98% via SFC (Chiralpak IG, 3x25 cm, 5 μm; 20% MeOH in CO2 RT1(min): 5.6; RT2(min): 8.0). Int.29 (0.67 g, 87.18%) was isolated as a brown solid. LCMS (ESI+): m/z 343.1 (M+H+).1H NMR (400 MHz, DMSO-d6) δ 8.08 – 7.50 (m, 3H), 5.71 – 5.59 (m, 1H), 5.30 – 5.20 (m, 1H), 5.04 – 4.91 (m, 2H), 1.46 (s, 9H). Int.30: Preparation of (S)-2-(3-((tert-butoxycarbonyl)amino)-2-oxopyridin-1(2H)- yl)pent-4-enoic acid: Step 1: (R)-2-hydroxypent-4- [0230] A 1 eq) in AcOH (460 mL) and H2O (1840 mL) was connected to pump A, a solution of NaNO2 (170.80 g, 2.48 mol, 2.5 eq) in H2O (460 mL) was connected to pump B. The two pumps were adjusted to a flowrate of 6.5 mL/min to a FEP coil. The reaction was conducted at 40℃ for 5 min. TLC (Petroleum ether: EtOAc = 3:1, stained by KMnO4) showed starting material (Rf = 0.01) was consumed completely and a major spot (Rf = 0.40) was detected. The mixture was acidified by the slow addition of 1N HCl at 0 °C. The mixture was extracted with EtOAc (2000 mL x 3), washed with brine (2000 mL x 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give (R)-2-hydroxypent-4- enoic acid (65 g, 559.79 mmol, 56.53%) as a yellow liquid.1H NMR (400 MHz, CDCl3-d): δ 2.42 - 2.78 (m, 2 H) 4.37 (dd, J=4.8, 6.8 Hz, 1 H) 5.16 - 5.29 (m, 2 H) 5.70 - 5.94 (m, 1 H). Step 2: methyl (R)-2-hydroxypent-4-enoate: PATENT Attorney Docket No.052687-509001WO [0231] To a solution mmol, 1 eq) in MeOH (600 mL) was added SOCl2 (79.92 g, 671.75 mmol, 48.79 mL, 1.2 eq) at 0°C. Then the mixture was stirred at 20°C for 2 h. The resulting mixture was concentrated under reduced pressure to remove the MeOH. The residue was dissolved in EtOAc (300 mL), washed with brine (100 mL x 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give methyl (R)-2-hydroxypent-4-enoate (60 g, 461.04 mmol, 82.36%) as a yellow oil.1H NMR (400 MHz, CDCl3-d): δ 2.36 - 2.67 (m, 2 H) 3.79 (s, 3 H) 4.29 (dd, J=4.8, 6.4 Hz, 1 H) 5.05 - 5.23 (m, 2 H) 5.80 (m, 1 H)) 5.16 - 5.29 (m, 2 H) 5.70 - 5.94 (m, 1 H). Step 3: methyl (R)-2-(((trifluoromethyl) sulfonyl) oxy) pent-4-enoate: [0232] To a solution 230.52 mmol, 1 eq) in DCM (300 mL) was added pyridine (27.35 g, 345.78 mmol, 27.91 mL, 1.5 eq) and Tf2O (97.56 g, 345.78 mmol, 57.05 mL, 1.5 eq) at 0°C. Then the mixture was stirred at ambient temperature. TLC (pet. ether: EtOAc = 3:1) showed starting material (Rf = 0.50) was consumed completely and a major spot (Rf = 0.60) was detected. The reaction was quenched with the addition of H2O (1000 mL). the mixture was extracted with DCM (1000 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by FCC (SiO2, 0% - 20% EtOAc in pet. ether). Methyl (R)-2-(((trifluoromethyl) sulfonyl) oxy) pent-4-enoate (15 g, 57.21 mmol, 24.82%) was isolated as a pale-yellow oil.1H NMR (400 MHz, CDCl3-d): δ 2.56 - 2.77 (m, 2 H), 3.77 (s, 3 H), 5.08 (dd, J=4.8, 7.2 Hz, 1 H), 5.13 - 5.22 (m, 2 H), 5.60 - 5.74 (m, 1 H). Step 4: methyl (S)-2-(3-((tert-butoxycarbonyl) amino)-2-oxopyridin-1(2H)-yl) pent-4- enoate: PATENT Attorney Docket No.052687-509001WO [0233] To a eq) in dioxane (300 mL) was added (Boc)2O (97.12 g, 444.99 mmol, 102.23 mL, 2 eq), the mixture was stirred at 110°C. The mixture was concentrated, and the residue was purified by FCC (SiO2, 0-30% EtOAc in pet. ether. Tert-butyl (2-oxo-1,2-dihydropyridin-3-yl)carbamate (38.2 g, 179.07 mmol, 80.48%) was isolated as a white solid. LCMS (ESI+): m/z 155.1 (M-56+H+). 1H NMR (400 MHz, DMSO-d6): δ 1.45 (s, 9 H), 6.21 (t, J=6.8 Hz, 1 H), 7.03 (dd, J=1.6, 6.4 Hz, 1 H), 7.68 (s, 1 H), 7.79 (dd, J=1.2, 6.8 Hz, 1 H), 11.93 (br s, 1 H). [0234] To a solution of methyl tert-butyl (2-oxo-1,2-dihydropyridin-3-yl)carbamate (5 g, 23.78 mmol, 1 eq) and methyl (R)-2-(((trifluoromethyl)sulfonyl)oxy)pent-4-enoate (6.24 g, 23.78 mmol, 1 eq) in THF (50 mL) was added K2CO3 (3.29 g, 23.78 mmol, 1 eq). The reaction was stirred at 20°C until the consumption of starting material (LCMS). The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, then filtered and concentrated. The residue was purified by FCC (SiO2, 0 to 20% EtOAc in pet. ether. Methyl (S)-2-(3-((tert-butoxycarbonyl) amino)-2-oxopyridin-1(2H)-yl) pent-4- enoate (5.0 g, 15.18 mmol, 63.85%) was isolated as a pink oil. LCMS (ESI+): m/z 323.2 (M+H+).1H NMR (400 MHz, CDCl3-d): δ 1.50 (s, 9 H), 2.67 - 2.83 (m, 1 H), 2.92 - 3.03 (m, 1 H), 3.75 (s, 3 H), 4.99 - 5.13 (m, 2 H), 5.46 (dd, J=5.2, 6.8 Hz, 1 H), 5.57 - 5.75 (m, 1 H), 6.25 (t, J=7.2 Hz, 1 H), 6.91 (dd, J=1.6, 7.2 Hz, 1 H), 7.62 (s, 1 H), 7.97 (d, J=6.8 Hz, 1 H). Step 5: Int.30: [0235] To a - - oxopyridin-1(2H)- yl)pent-4-enoate (3.3 g, 10.24 mmol, 1 eq) in EtOAc (70 mL) was added MgI2 (5.69 g, 20.47 mmol, 1.29 mL, 2 eq) and stirred at 40°C for 2 h. Upon consumption of starting material (LCMS), the reaction was quenched by the addition of water (200 mL) and extracted with PATENT Attorney Docket No.052687-509001WO EtOAc (80 mL x 3). The aqueous phase acidified by 1M HCl at 0 °C. The mixture was extracted with EtOAc (100 mL x 3). The combined organics were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give Int.30 (2.41g, 9.53 mmol, 93.14%) as a yellow gum. LCMS (ESI+): m/z 253.0 (M-56+H+).1H NMR (400 MHz, CDCl3-d): δ 1.50 (s, 9 H), 2.78-2.86 (m, 1 H), 2.98-3.04 (m, 1 H), 5.01 - 5.14 (m, 2 H), 5.39 (dd, J = 5.2, 10.4 Hz, 1 H), 5.57 - 5.73 (m, 1 H), 6.31 (t, J = 7.2 Hz, 1 H), 6.94 (dd, J = 1.2, 6.8 Hz, 1 H), 7.66 (s, 1 H), 8.04 B. Representative Procedures for Preparing Compounds of Formula (I) [0236] The following subsections describe procedures for preparing compounds of Formula (I). It is understood that compounds of Formula (I) can be prepared using variety of synthetic routes. The following procedures are meant to be illustrative, not limiting. Generally, compounds of Formula (I) are prepared by synthesizing a macrocyclic portion of the compound and completing final synthetic steps to obtain compounds of Formula (I). The final synthetic steps include optional modifications (e.g., Phe Suzuki coupling) and tail addition (comprising the R3, R4a/b/c variable positions of Formula (I)). The macrocyclic synthesis procedures described herein include Methods A and B. The final synthesis procedures described herein include Methods 1-4. 1. Macrocycle Synthesis Procedures a. Method A Generic Procedure for Method A: R6d R6d HO O O N O m8 m8 PATENT Attorney Docket No.052687-509001WO Step 1: Tert-butyl (S)-(3-(2-bromo-5-fluorophenyl)-1-(hex-5-en-1-yl(methyl)amino)-1- oxopropan-2-yl)(methyl)carbamate (500): [0237] 1.3 eq,) in DMF (500 mL) was added HATU (48.5 g, 127.5 mmol, 1.5 eq) and DIPEA (55.0 g, 425.3 mmol, 74.1 mL, 5 eq) at 0 °C. The mixture was removed from the cooling bath and stirred at 25 °C until LCMS analysis showed the complete consumption of starting material. The reaction was added into ice water (1000 mL), then extracted with EtOAc (1000 mL × 2), the combined organic layers were washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give crude product which was purified by column chromatography (SiO2, EtOAc:Hexanes; 0-60%) to yield 500: (37 g, 78.5 mmol, 92.3% yield) as a yellow oil. LCMS (ESI+): m/z 493.1 (M+Na+) Step 2-3: Tert-butyl ((S)-1-(((S)-3-(2-bromo-5-fluorophenyl)-1-(hex-5-en-1- yl(methyl)amino)-1-oxopropan-2-yl)(methyl)amino)-4-methyl-1-oxopentan-2- yl)carbamate (502): PATENT Attorney Docket No.052687-509001WO (80 mL) at 0 °C. The mixture was removed from the cooling bath and stirred at 25 °C until LCMS analysis showed the complete consumption of starting material. The reaction mixture was concentrated under reduced pressure to give 501 (38 g, crude, TFA) as a light-yellow oil. LCMS (ESI+): m/z 371.1 (M+H+) [0239] To a solution of 501 (38 g, 78.3 mmol, 1 eq, TFA salt) and Boc-Leu-OH (19.9 g, 86. mmol, 1.1 eq) in DMF (1000 mL) was added HATU (44.7 g, 117.5 mmol, 1.5 eq) and DIEPA (50.6 g, 391.5 mmol, 68.2 mL, 5 eq) at 0 °C. The mixture was removed from the cooling bath and stirred at 25 °C until LCMS analysis showed the complete consumption of starting material. The reaction was added into ice water 2000 mL, then extracted with EtOAc (2000 mL × 2), the combined organic layers were washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give crude product which was purified by column chromatography (SiO2, EtOAc:Hexanes 0-50%) to give 502 (45 g) as a yellow oil. LCMS (ESI+): m/z 606.2 (M+Na+) Step 4-5: Tert-butyl (1-((S)-1-(((S)-1-(((S)-3-(2-bromo-5-fluorophenyl)-1-(hex-5-en-1- yl(methyl)amino)-1-oxopropan-2-yl)(methyl)amino)-4-methyl-1-oxopentan-2-yl)amino)- 1-oxopent-4-en-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate (504): g, was was added. The reaction was continued until complete deprotection of the Boc group was PATENT Attorney Docket No.052687-509001WO observed by LCMS. The volatile solvent was removed, and the residue was suspended in Toluene (20 mL). The volatile solvent was again removed to ensure complete removal of excess TFA. The crude deprotection product, 503, was used without further purification. LCMS (ESI+): m/z 484.2 (M+H+) [0241] 503 (4.5 g, 1 Eq, 7.7 mmol), Int.30 (2.6 g, 1.1 Eq, 8.5 mmol) and HATU (3.2 g, 1.1 Eq, 8.5 mmol) were weighed into a round bottom flask. the solids were dissolved in DMF (20 mL) and DIPEA (3.5 g, 4.7 mL, 3.5 Eq, 27 mmol) was added. The reaction mixture was confirmed to be basic (pH indicator), and the reaction was stirred at room temperature until the consumption of starting material (monitored by LCMS). Water (50 mL) was added, and the aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated. The residue was purified by FCC (SiO2, EtOAc in Hex 0 to 80%) 504 (2.37 g, 3.06 mmol, 40 %) was isolated as a thick oil. LCMS (ESI+): m/z 774.5 (M+H+) Step 6: Tert-butyl (1-((3S,6S,9S)-3-(2-bromo-5-fluorobenzyl)-6-isobutyl-1,4-dimethyl- 2,5,8-trioxo-1,4,7-triazacyclohexadec-11-en-9-yl)-2-oxo-1,2-dihydropyridin-3- yl)carbamate (505): , and purged with N2 for 0.5 hr. Dichloro(1,3-dimesityl-2-imidazolidinylidene)(2- isopropoxybenzylidene)ruthenium (288 mg, 0.15 Eq, 459 μmol) was added and, the mixture was quickly capped and stirred at 50 °C until LCMS analysis showed the complete consumption of starting material. The reaction mixture was concentrated under reduced pressure to give a thick residue. The crude product was purified by flash chromatography (C18, 25-80% MeCN in water +0.1% TFA).505 was isolated as a beige solid, LCMS (ESI+): m/z 746.4 (M+H+). PATENT Attorney Docket No.052687-509001WO Step 7: Tert-butyl (1-((3S,6S,9S)-3-(2-bromo-5-fluorobenzyl)-6-isobutyl-1,4-dimethyl- 2,5,8-trioxo-1,4,7-triazacyclohexadecan-9-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate (506): (49.3 mg, 0.15 Eq, 217 µmol) was added. Air was evacuated from the system and replaced with an atmosphere of H2. The reaction was stirred vigorously until the consumption of starting material was observed by LCMS analysis. The reaction mixture was filtered over a pad of celite. The filter was washed with EtOAc (2 x 10 mL) and the filtrate was concentrated to obtain a quantitative yield of 506 (~1.1 g, ~1.45 mmol) as an off white solid. The product was used in the next reactions with no additional purification. LCMS (ESI+): m/z 748.5 (M+H+). b. Method B Generic Procedure for Method B: PATENT Attorney Docket No.052687-509001WO Representative Procedure for Method B Steps 1-7: (3S,6S,9S)-3-(2,5-dichlorobenzyl)-9-(2-((2S,4R)-1-(3,3-difluoro-1- (trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidin-2-yl)-4-oxo-3,4- dihydro-5H-imidazo[4,5-c]pyridin-5-yl)-6-isobutyl-1,4-dimethyl-1,4,7- triazacyclohexadecane-2,5,8-trione (Example 3): [0244] Steps 1-7 outlined in Steps 1-7 of Method A. Int.1, Int. 3, and Int. 25 were used as starting materials. Example 3 was isolated as a fluffy white solid. LCMS (ESI+): m/z 904.40 (M+H+). 2. Final Synthesis Procedures to prepare Compounds of Formula (I) PATENT Attorney Docket No.052687-509001WO a. Method 1 Generic Procedure for Method 1 R6d R 6d N O N 6 8b B O 1. deBoc X 6 R 8b B m8 Tert-butyl (1-((3S,6S,9S)-3-((5-chloro-2-cyclopropoxypyridin-3-yl)methyl)-6-isobutyl- 1,4-dimethyl-2,5,8-trioxo-1,4,7-triazacyclohexadecan-9-yl)-2-oxo-1,2-dihydropyridin-3- yl)carbamate: [0245] The starting using Method A using with Int.2, Int.7, and Int.30 as starting materials. LCMS (ESI+): m/z 743.4 (M+H+). Step 1: (2S,4R)-N-(1-((3S,6S,9S)-3-((5-chloro-2-cyclopropoxypyridin-3-yl)methyl)-6- isobutyl-1,4-dimethyl-2,5,8-trioxo-1,4,7-triazacyclohexadecan-9-yl)-2-oxo-1,2- PATENT Attorney Docket No.052687-509001WO dihydropyridin-3-yl)-1-(3,3-difluoro-1-(trifluoromethyl)cyclobutane-1-carbonyl)-4- fluoropyrrolidine-2-carboxamide (Example 6): to sit for 1 hour. The solution was concentrated by rotary evaporation, resuspended in toluene (2 mL) and concentrated again to remove excess TFA. (3S,6S,9S)-9-(3-amino-2-oxopyridin- 1(2H)-yl)-3-((5-chloro-2-cyclopropoxypyridin-3-yl)methyl)-6-isobutyl-1,4-dimethyl-1,4,7- triazacyclohexadecane-2,5,8-trione (508) (TFA salt, 55 mg, 73 µmol) was isolated as an oil and used with no further purification. LCMS (ESI+): m/z 643.4 (M+H+). [0247] 508 (TFA salt, 55 mg, 73 µmol), Int.22 (35 mg, 1.5 Eq, 0.11 mmol), HATU (41 mg, 1.5 Eq, 0.11 mmol), and DIPEA (38 mg, 51 µL, 4 Eq, 0.29 mmol) were dissolved in DMF (1.5 mL). The pH was checked with indicator paper, and DIPEA was added in 1 Eq portions until basic. The reaction was stirred for 20 hours, diluted with 1.5 mL acetonitrile, and directly purified by reverse-phase chromatography (40 to 100% acetonitrile in water, 0.1% FA) to yield Example 6 (10 mg, 10.5 µmol, 15%) as a fluffy white solid. LCMS (ESI+): m/z 944.39 (M+H+). b. Method 2
PATENT Attorney Docket No.052687-509001WO Generic Procedure for Method 2 Tert-butyl (1-((3S,6S,9S)-3-(2-bromo-5-chlorobenzyl)-6-isobutyl-1,4-dimethyl-2,5,8- trioxo-1,4,7-triazacyclohexadecan-9-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate (509): [0248] The starting using Method A with Int. 2, Int.4, and Int.30 as starting materials. LCMS (ESI+): m/z 764.2 (M+H+).1H NMR (400 MHz, MeOD-d4): δ 0.72 (d, J=6.44 Hz, 3 H), 0.95 (d, J=6.56 Hz, 3 H), 1.02 - 1.11 (m, 1 H), 1.18 - 1.27 (m, 1 H), 1.32 - 1.49 (m, 7 H), 1.51 (s, 10 H), 1.52 - 1.61 (m, 3 H), 1.63 - 1.80 (m, PATENT Attorney Docket No.052687-509001WO 2 H), 2.12 - 2.25 (m, 1 H), 2.68 (br d, J=13.35 Hz, 1 H), 2.85 (s, 3 H), 2.96 (s, 3 H), 3.22 - 3.29 (m, 1 H), 3.33 - 3.41 (m, 1 H), 4.29 - 4.48 (m, 2 H), 5.41 - 5.52 (m, 1 H), 6.33 (t, J=7.33 Hz, 1 H), 7.22 (dd, J=8.52, 2.56 Hz, 1 H), 7.27 (d, J=2.50 Hz, 1 H), 7.45 (dd, J=7.15, 1.55 Hz, 1 H), 7.57 (d, J=8.46 Hz, 1 H), 7.93 (d, J=7.15 Hz, 1 H). Step 1: Tert-butyl (1-((3S,6S,9S)-3-(2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-5- chlorobenzyl)-6-isobutyl-1,4-dimethyl-2,5,8-trioxo-1,4,7-triazacyclohexadecan-9-yl)-2- oxo-1,2-dihydropyridin-3-yl)carbamate (510): mg, 4 Eq, 0.31 mmol), and Int.11(39 mg, 2.0 Eq, 0.16 mmol) was weighed into a vial and dissolved in 4:11,4-Dioxane:Water (2 mL). The reaction was degassed for 15 minutes at 25 °C then heated to 80 °C for 1 hour or until the complete consumption of starting material (monitored by LCMS). The reaction was quenched with minimal 1M HCl, filtered, and directly purified via RP-HPLC (20-80% MeCN in water +0.1% TFA). 510 (30 mg, 37.1 μmol, 47.6%) LCMS (ESI+): m/z 809.4 (M+H+). Steps 2-3: (2S,4R)-N-(1-((3S,6S,9S)-3-(2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-5- chlorobenzyl)-6-isobutyl-1,4-dimethyl-2,5,8-trioxo-1,4,7-triazacyclohexadecan-9-yl)-2- oxo-1,2-dihydropyridin-3-yl)-1-(3,3-difluoro-1-(trifluoromethyl)cyclobutane-1- carbonyl)-4-fluoropyrrolidine-2-carboxamide (Example 20): PATENT Attorney Docket No.052687-509001WO until the deprotection was complete (monitored by LCMS). The volatile solvent was completely removed via evaporation with co-solvent to afford a quantitative yield of 511. The product was used with no further purification. LCMS (ESI+): m/z 709.4 (M+H). [0251] 511 as the TFA salt (26 mg, 1 Eq, 31.9 μmol) and Int.22 (12.2 mg, 1.2 Eq, 38.2 μmol) were dissolved in DMF (0.5 mL). DIPEA (24.7 mg, 6 Eq, 191 μmol) and HATU (14.5 mg, 1.2 Eq, 38.2 μmol) were added sequentially and the reaction was continued until the consumption of starting material (monitored by LCMS). The reaction mixture was neutralized to pH ~7 with 1N HCl and directly purified by RP-HPLC (C18, 45% - 75% MeCN in H2O with 0.5% formic acid). Example 20 (9.4 mg, 9.3 μmol 29.2%) was obtained as a white solid after lyophilization. LCMS (ESI+): m/z 1010.45 (M+H).
PATENT Attorney Docket No.052687-509001WO c. Method 3 Generic Procedure for Method 3 PATENT Attorney Docket No.052687-509001WO Representative Experimental for Method 3: Example 1 509: [0252] The synthesis above. Steps 1-2: (2S,4R)-N-(1-((3S,6S,9S)-3-(2-bromo-5-chlorobenzyl)-6-isobutyl-1,4-dimethyl- 2,5,8-trioxo-1,4,7-triazacyclohexadecan-9-yl)-2-oxo-1,2-dihydropyridin-3-yl)-1-(3,3- difluoro-1-(trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxamide (513): stirred until the deprotection was complete (monitored by LCMS). The volatile solvent was completely removed to afford a quantitative yield of 512. LCMS (ESI+): m/z 664.4 (M+H+). [0254] 512 (165mg, 1 Eq, 235 μmol, HCl salt) and Int.22 (97.5 mg, 1.3 Eq, 306 μmol) were dissolved in EtOAc (1 mL). Pyridine (112 mg, 114 μL, 6 Eq, 1.41 mmol). Once dissolved, a 50 wt.% solution of T3P in EtOAc (97.2 mg, 1.3 Eq, 306 μmol) was added and the reaction was continued until the consumption of starting material (monitored by LCMS). Once complete, the reaction was diluted with EtOAc (10 mL), extracted sequentially with water (5 ml), 1 N HCl (5 ml), and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified by RP-HPLC (C18, 45% to 75% PATENT Attorney Docket No.052687-509001WO MeCN/H2O with 0.5% formic acid).513 (200 mg, 207 μmol, 75 %) was obtained as a white solid after lyophilization. LCMS (ESI+): m/z 965.4 (M+H). Step 3: (2S,4R)-N-(1-((3S,6S,9S)-3-((4-chloro-4'-((2R,6R)-2,6-dimethylmorpholino)- [1,1'-biphenyl]-2-yl)methyl)-6-isobutyl-1,4-dimethyl-2,5,8-trioxo-1,4,7- triazacyclohexadecan-9-yl)-2-oxo-1,2-dihydropyridin-3-yl)-1-(3,3-difluoro-1- (trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxamide (Example 1): mg, 2.0 Eq, 414 μmol) and PdCl2(dppf)•CH2Cl2 (16.9 mg, 0.1 Eq, 20.7 μmol) were dissolved in 4:1 Dioxane/Water (4 mL). The reaction was degassed for 10 min with Ar and then heated to 80 °C until the complete consumption of starting material (monitored by LCMS). The vial was then cooled and adjusted to pH ~7 with 1N HCl. The homogeneous solution was directly purified by RP-HPLC (C18, 50% to 85% MeCN/H2O with 0.5% formic acid) to obtain Example 1: (14.6 mg, 13.6 μmol, 6.5 %) as a white solid after lyophilization. LCMS (ESI+): m/z 1077.01 (M+H). Generic Procedure for Method 4 PATENT Attorney Docket No.052687-509001WO Representative Procedure for Method 4: Example 30 O Cl B O Cl N N O - - - (trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidin-2-yl)-4-oxo-3,4-dihydro- 5H-imidazo[4,5-c]pyridin-5-yl)-6-isobutyl-1,4-dimethyl-1,4,7-triazacyclohexadecane- 2,5,8-trione (514): [0256] The starting Method B with Int. 2, Int.4, and Int.25 as starting materials. LCMS (ESI+): m/z 962.30 (M+H). Step 1: (3S,6S,9S)-3-(5-chloro-2-(6-morpholinopyridin-3-yl)benzyl)-9-(2-((2S,4R)-1-(3,3- difluoro-1-(trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidin-2-yl)-4-oxo-3,4- dihydro-5H-imidazo[4,5-c]pyridin-5-yl)-6-isobutyl-1,4-dimethyl-1,4,7- triazacyclohexadecane-2,5,8-trione (Example 30): PATENT Attorney Docket No.052687-509001WO [0257] Step 1 of Method 4 was performed identically to Step 1 of Method 2 using 514 and Int.19 as starting materials. Example 30 was isolated as a white solid. LCMS (ESI+): m/z 1046.05 (M+H). 3. Exemplary Compounds – Preparation Summary Tables [0258] Table 2, below, provides information on the methods used to prepare the exemplified compounds in the current application. This table includes a column listing the 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 Example Number Macrocycle Synthesis Final Synthesis 1 Method A with Int.2, Int.4, Method 3 Int.30 2 Method A with Int.2, Int.4, Method 2 with Int.20, int.23 Int.30 3 N/A Method B with Int.1, Int.3, Int.25 4 Method A with Int.2, Int.4, Method 2 with Int.5, Int.22 Int.30 5 Method A with Int.2, Int.4, Method 2 with Int.6, Int.22 Int.30 6 Method A with Int.2, Int.7, Method 1 Int.30 7 Method A with Int.2, Int.7, Method 1 with Int.23 Int.30 8 Method A with Int.2, Int.7, Method 1 with Int..24 Int.30 9 Method A with Int.2, Int.4, Method 2 with Int.6, Int.22 Int.30 10 Method A with Int.2, Int.13, Method 2 with Int.8, Int.22 Int.30 11 Method A with Int.2, Int.13, Method 2 with Int.9, Int.22 Int.30 12 Method A with Int.2, Int.13, Method 2 with Int.10, Int.22 Int.30 13 Method A with Int.2, Int.13, Method 2 with Int.11, Int.22 Int.30 PATENT Attorney Docket No.052687-509001WO Example Number Macrocycle Synthesis Final Synthesis 14 Method A with Int.2, Int.13, Method 2 with Int.12, Int.22 Int.30 15 Method A with Int.2, Int.13, Method 2 with Int.5, Int.22 Int.30 16 Method A with Int.2, Int.13, Method 2 with Int.14, Int.22 Int.30 17 Method A with Int.2, Int.4, Method 2 with Int.8, Int.22 Int.30 18 Method A with Int.2, Int.4, Method 2 with Int.9, Int.22 Int.30 19 Method A with Int.2, Int. 4, Method 2 with Int.10, Int.22 Int.30 20 Method A with Int.2, Int.4, Method 2 Int.30 21 Method A with Int.2, Int.4, Method 2 with Int.12, Int.22 Int.30 22 Method A with Int.2, Int.4, Method 2 with Int.14, Int.22 Int.30 23 Method A with Int.2, Int.15, Method 1 with Int.22 Int.30 24 Method A with Int.2, Int.15, Method 1 with Int..23 Int.30 25 Method A with Int.2, Int.15, Method 1 with Int..24 Int.30 26 N/A Method B with Int.2, Int.7, Int.25 27 Method A with Int.2, Int.4, Method 2 with Int.16, Int.22 Int.30 28 Method A with Int.2, Int.4, Method 2 with Int.18, int.22 Int.30 29 Method B with Int.2, Int.4, Method 4 with Int.16 Int.25 30 Method B with Int.2, Int.4, Method 4 with Int.19 Int.25 31 Method A with Int.2, Int.17, Method 1 with Int.22 Int.30 32 Method A with Int.2, Int.17, Method 1 with Int.24 Int.30 33 Method A with Int.2, Int.4, Method 3 with Int.20, int.22 Int.30 34 Method A with Int.2, Int.4, Method 1 with Int.22 Int.27 PATENT Attorney Docket No.052687-509001WO Example Number Macrocycle Synthesis Final Synthesis 35 Method A with Int.2, Int.4, Method 1 with Int.22 Int.28 36 Method A with Int.2, Int.4, Method 1 with Int.22 Int.29 [0259] Table 3, below, provides the expected (Exact MW) and observed molecular weight for each exemplary compound listed in Table 2. Table 3: Analytical Data for Exemplary Compounds of Table 2 Ex. Number Exact Mass Observed m/z 1 1075.48 1076.66 2 1024.5 1025.64 3 903.31 904.40 4 966.4 967.39 5 992.42 993.43 6 943.38 944.39 7 907.4 908.42 8 937.41 938.41 9 976.44 977.44 10 990.46 991.46 11 1001.44 1002.46 12 987.42 988.42 13 993.46 994.47 14 976.44 977.47 15 950.43 951.45 16 1006.46 1007.47 17 1006.43 1007.43 18 1017.41 1018.20 19 1003.39 1004.41 20 1009.43 1010.45 21 992.42 993.43 22 1022.43 1023.45 23 967.39 968.40 24 931.41 932.43 25 961.42 962.42 PATENT Attorney Docket No.052687-509001WO Ex. Number Exact Mass Observed m/z 26 940.38 941.14 27 1030.36 1030.94 28 1056.38 1056.92 29 1053.38 1053.99 30 1045.44 1046.05 31 959.36 960.01 32 953.39 954.04 33 1060.48 1061.22 34 978.29 979.23 35 978.29 979.09 36 998.23 999.18 [0260] Table 4, below, provides the full chemical structure for each exemplified compound in Table 2. Table 4: Chemical Structure for Exemplary Compounds Described in Table 2 Ex. Chemical Structure Ex. Chemical Structure No. No. 1 2 3 4 5 6 Cl N O F N O H N F H N N O F N N O O O O F F F PATENT Attorney Docket No.052687-509001WO Ex. Chemical Structure Ex. Chemical Structure No. No. 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 PATENT Attorney Docket No.052687-509001WO Ex. Chemical Structure Ex. Chemical Structure No. No. 23 24 25 26 27 28 29 30 31 Cl N O 32 F N O N H H F N S F N N N O O O O F F F 33 34 35 36 C. Biological Examples PATENT Attorney Docket No.052687-509001WO 1. Fluorescence Polarization Assay [0261] Binding affinity for the compounds of Formula (I) were determined by Fluorescence Polarization (FP) competitive assay based on previously established protocols (Andrews et. al., Org Biomol Chem., 2004.2(19):2735-41.; Premnath et. al., J Med Chem., 2015.58(1):433-42.) with modifications as described below. 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. 14-475). [0262] 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. After experimental plates are set, they were equilibrated by gentle mixing by placing them on an orbital shaker at 100 rpm for 2 hours at rt and then read on a SpectraMax i3X Multi-Mode Microplate Detection platform. [0263] Affinity of the Cyclin/Cdk complexed for the fluorescent labeled probe was determined by adding increasing concentration of each protein complex in buffer containing a carboxyfluorescein labeled probe (FAM probe) at 2 nM (preparation of FAM probe is described below). The half maximal concentration of protein needed for the maximal FP signal were 2 nM for Cyclin A2/Cdk2, 9 nM for Cyclin B1/Cdk1 and 3 nM for Cyclin E1/Cdk2. Methods to prepare the FAM probe are described in the heading below. [0264] 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 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 IC50 are the average of 2-3 independent experiments. Data from these assays are reported in Table 5. Table 5: Cyclin A, B, and E Activity Data of Exemplary Compounds Cyclin A Cyclin B Cyclin E Example FP IC50 FP IC50 FP IC50 Number (µM) (µM) (µM) 1 0.09 0.02 20.00 2 0.02 0.02 1.77 PATENT Attorney Docket No.052687-509001WO Cyclin A Cyclin B Cyclin E Example FP IC50 FP IC50 FP IC50 Number (µM) (µM) (µM) 0.07 0.02 20.00 0.02 0.02 1.45 0.02 0.02 1.58 0.09 0.02 1.10 0.05 0.02 0.30 0.08 0.02 0.21 0.02 0.02 0.33 0 0.02 0.02 0.34 1 0.03 0.02 0.67 2 0.07 0.02 3.23 3 0.03 0.02 1.30 4 0.04 0.02 0.93 5 0.02 0.02 0.41 6 0.02 0.02 0.33 7 0.03 0.02 6.67 8 0.02 0.02 2.24 9 0.03 0.02 20.00 0 0.02 0.02 3.85 1 0.03 0.02 3.04 2 0.02 0.02 1.41 3 0.03 0.02 1.45 4 0.02 0.02 0.64 5 0.04 0.02 0.36 6 0.07 0.02 2.22 7 0.03 0.02 20.00 8 0.03 0.02 20.00 9 0.05 0.02 20.00 0 0.03 0.02 20.00 1 0.09 0.02 0.92 2 0.09 0.02 0.22 3 0.02 0.02 2.92 4 0.03 0.02 2.00 5 0.15 0.02 6.67 6 0.09 0.02 20.00 PATENT Attorney Docket No.052687-509001WO Preparation of Fluorescent Probe (FAM Probe) by cyclization, fluorescent labeling, and deprotection in solution. [0266] To load Fmoc-Glycine onto ~50 mg of CTC resin, Fmoc-Glycine (G), CAS#29022- 11-5, (4 equiv.) was dissolved in 1.0 mL of anhydrous NMP. Neat DIEA (8 equiv.) was 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. 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 washed with 1.0 mL DMF three times. To remove Fmoc, 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. [0267] A solution of Fmoc-L-2,5-dichlorophenylalanine-OH (25ClF), CAS#1260614-80-9, (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 then the resin was washed with 1.0 mL of DMF three times. To remove Fmoc, 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. [0268] To N-Methylate the amine of 25ClF, 2,6-lutidine (6 equiv.) dissolved in 0.5 mL of anhydrous DCE was added to the resin.2-nitrobenzenesulfonyl chloride (5 equiv.) dissolved in 0.5 mL anhydrous toluene was added to the resin and then was agitated at 40 to 45°C for 10 to 15 min. The mixture was drained, then the resin was washed with 1.0 mL of anhydrous PATENT Attorney Docket No.052687-509001WO toluene three times. The method was repeated twice. Triphenylphosphine (10 equiv.) dissolved in 0.7 mL anhydrous toluene was added to the resin. Dry methanol (MeOH), (20 equiv.) was added to the resin. Azodicarboxylate (10 equiv.) was added to the resin and the mixture was agitated at 45°C for 30 min. The mixture was drained and the resin was washed with 1.0 mL of anhydrous DMF three times. Alkylation was repeated twice. The nosyl group was then deprotected. A solution of2-mercaptoethanol (5 equiv.) and 1,8- Diazabicyclo[5.4.0]undec-7-ene (5 equiv.) in 1.0 mL NMP was added to the resin and the mixture was agitated at 45°C for 10 min. The mixture was drained and then the resin was washed with 1.0 mL of anhydrous DMF three times. Deprotection was repeated twice. [0269] 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 remove Fmoc, 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. [0270] Fmoc-L-Lysine(Mtt)-OH (KMtt), CAS#167393-62-6, (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 then the resin was washed with 1.0 mL of DMF three times. To remove Fmoc, 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. [0271] Fmoc-L-Arginine(Pbf)-OH (RPbf), CAS#154445-77-9, (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 then the resin was washed with 1.0 mL of DMF three times. To remove Fmoc, 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. [0272] Fmoc-L-Lysine(Boc)-OH (KBoc), CAS#71989-26-9, (4 equiv.), HATU (4 equiv.), and DIEA (8 equiv.) in 1.0 mL of anhydrous NMP was prepared. The mixture was allowed to PATENT Attorney Docket No.052687-509001WO 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 remove Fmoc, 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. [0273] Fmoc-L-Alanine-OH (A), CAS#35661-39-3, (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 then the resin was washed with 1.0 mL of DMF three times. To remove Fmoc, 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. [0274] Fmoc-L-Histidine(Trt)-OH (HTrt), CAS#109425-51-6, (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 then the resin was washed with 1.0 mL of DMF three times. To remove Fmoc, 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. [0275] 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. [0276] To cleave peptide from CTC resin and simultaneously deprotect the Mtt protecting group, approximately 2 mL of a solution of 24% HFIP, 2% TIPS, in DCM was added to the polystyrene resin in a solid phase reaction vessel. The contents were shaken for 1 hour. The cleavage solution was filtered into a 50 mL conical vial. The cleaved resin was washed with an additional 2 mL of DCM and the wash was collected in the conical vial. The solution was evaporated in a Genevac. The linear peptide was purified via reverse-phase HPLC using an Acetonitrile/Water gradient with 0.05% formic acid and the purified fractions were pooled and lyophilized to yield white powder of intermediate X (M/z observed = 1968.65 [M+H]+). PATENT Attorney Docket No.052687-509001WO [0277] 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 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- deprotection steps. The cyclic peptide was then purified via reverse phase HPLC using an Acetonitrile/Water gradient with 0.05% formic acid. The purified fractions were pooled and lyophilized to yield intermediate Y (M/z observed = 1485.94 [M+Z]+). PATENT Attorney Docket No.052687-509001WO [0278] The probe was fluorescently labeled via a peptide coupling in solution. A solution of 5-carboxyfluorescein (CAS#76823-03-5, FAM) (4 equiv.), EDC (4 equiv.), HOAt (3.9 equiv.) and DIEA (8 equiv.) in 1.0 mL of anhydrous DCM was prepared. The mixture was allowed to pre-activate at rt for 5 min. Intermediate Y was added to the coupling solution, and the reaction was agitated at rt until starting material was not observed by LCMS, resulting in the formation of Intermediate Z (M/z observed = 1844.29 [M+Z]+). [0279] The Boc and Pbf protecting groups were removed from the cyclic intermediate Z by dissolving the cyclic peptide in a 1 mL solution of 90% TFA, 5% TIPS, 5% DCM and agitating for 1 hour. The reaction was monitored by LCMS for the disappearance of starting material. Upon completion, the reaction was concentrated. The crude material was co- evaporated with DCE (5 mL x 2), and then purified via reverse phase-HPLC to yield fluorescent probe (FAM probe) (M/z observed = 1492.14 [M+Z]+ , 0.7 mg, 99% purity by HPLC). 2. MTT Proliferation Assay [0280] MTT proliferation assay was used to determine the 50% growth inhibition (GI50) of disclosed compounds.5 x 103 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 10µM. Cells were exposed to compound for a sufficient time to allow 3-4 cell doublings (3 days (WI-38); 5 days (NCI-H1048 and OVCAR3)). Roscovitine and staurosporine were used as plate controls. At the end of the compound incubation, MTT reagent (TACS MTT Cell PATENT Attorney Docket No.052687-509001WO Proliferation Assay R&D Systems Catalog #4890-025-K) was added and assay carried out. Results are summarized in Table 6 Table 6: Cellular Activity Data of Exemplary Compounds Example H1048 GI50 OVCAR3 WI-38 GI50 Number (µM) GI50 (µM) (µM) 1 0.01 0.03 20.00 2 0.02 0.03 20.00 3 0.14 0.13 20.00 4 0.01 0.01 20.00 5 0.01 0.01 20.00 6 0.02 0.04 20.00 7 0.03 0.04 20.00 8 0.01 0.01 20.00 9 0.01 0.01 20.00 10 0.01 0.01 20.00 11 0.01 0.01 20.00 12 0.01 0.02 20.00 13 0.01 0.01 20.00 14 0.01 0.01 20.00 15 0.01 0.01 20.00 16 0.01 0.01 20.00 17 0.01 0.01 20.00 18 0.01 0.01 20.00 19 0.02 0.02 12.50 20 0.01 0.01 20.00 21 0.01 0.01 20.00 22 0.01 0.01 20.00 23 0.01 0.01 20.00 24 0.01 0.01 20.00 25 0.01 0.01 20.00 26 0.06 0.08 20.00 27 0.01 0.01 20.00 28 0.01 0.01 20.00 29 0.08 0.08 20.00 30 0.05 0.05 20.00 31 0.03 0.03 20.00 32 0.01 0.01 20.00 PATENT Attorney Docket No.052687-509001WO Example H1048 GI50 OVCAR3 WI-38 GI50 Number (µM) GI50 (µM) (µM) 33 0.01 0.01 2.92 34 0.11 0.13 35 0.30 0.30 36 .019 0.26 [0281] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

Claims

PATENT Attorney Docket No.052687-509001WO WHAT IS CLAIMED IS: 1. A compound of Formula (I) (I) wherein 3 R is (a) C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, or C1-8 haloalkyl, each substituted with 0, 1, 2, 3, 4, or 5 R3a, (b) C3-12 cycloalkyl substituted with 0, 1, 2, 3, 4, or 5 R3b, 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, 4, or 5 R3c; (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 R3g; each R3a is independently –OH, C1-6 alkoxy, C1-6 haloalkoxy, –O–(CH2CH2O)1-4–C1-4 alkyl, –O–(CH2CH2O)1-4–heterocycloalkyl, C1-3 haloalkoxy, –NR3a1R3a2, –O–C(O)C1-6 alkyl, C3-6 cycloalkyl, phenyl, or heteroaryl, wherein each heterocycloalkyl has 4 to 6 ring members and 1 to 3 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; each R3b is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo, C1-6 haloalkyl, cyano, –OH, C1-6 alkoxy, C1-6 haloalkoxy, –NR3b1R3b2, –N(R3b3)C(O)R3b4, phenyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; each R3c is independently C1-6 alkyl, halo, C1-6 haloalkyl, cyano, oxo, or C3-6 cycloalkyl; each R3g is independently C1-6 alkyl, halo, C1-6 haloalkyl, or C3-6 cycloalkyl; each R3a1, R3a2, R3b1, R3b2, and R3b3 is independently H or C1-6 alkyl; PATENT Attorney Docket No.052687-509001WO each R3b4 is C1-6 alkyl or C1-6 haloalkyl; R4a is H or C1-6 alkyl; R4b and R4c are each independently H, C1-6 alkyl, –C1-6 alkyl–OH, C1-6 haloalkyl, –NR4c1R4c2, –C1-6 alkyl–NR4c1R4c2, C3-6 cycloalkyl, –C1-6 alkyl–C3-6 cycloalkyl, heterocycloalkyl, –C1-6 alkyl–heterocycloalkyl, phenyl, –C1-6 alkyl–phenyl, heteroaryl, or –C1-6 alkyl–heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members and 1 to 3 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; alternatively, R4c and R4a together with the carbon and nitrogen to which each is attached combine to form a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, 3, or 4 R4a1; each R4c1 and R4c2 are independently C1-6 alkyl or C2-6 alkoxyalkyl; each R4a1 is independently C1-6 alkyl, –OH, –C1-6 alkyl–OH, C1-6 alkoxy, halo, or –N(R4a2)S(O)2–C1-4 alkyl; R4a2 is H or C1-6 alkyl; alternatively, two R4a1 groups on adjacent ring atoms combine to form a phenyl ring substituted with 0, 1, or 2 R4a3; each R4a3 is independently C1-6 alkyl, –OH, –C1-6 alkyl–OH, C1-6 alkoxy, or halo; X5 is a bond or –C(O)NR5d–; R5d is H or C1-6 alkyl; ring C is a heteroaryl having 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein the heteroaryl is substituted with 0, 1, 2, 3, or 4 R5e; each R5e is independently C1-6 alkyl, –OH, halo, C1-6 haloalkyl, or oxo; X6 is C6-7 alkylene or C6-7 alkenylene; R6b is H or C1-6 alkyl; R6d is H, C1-6 alkyl, C1-6 deuteroalkyl, –OH, or C2-6 alkoxyalkyl; R7a is H or C1-6 alkyl; R7b and R7c are each independently H, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 alkyl–OH, C3-6 cycloalkyl, or –C1-6 alkyl–C3-6 cycloalkyl; R8a is H, C1-6 alkyl, C1-6 deuteroalkyl, C2-6 alkoxyalkyl, C3-6 cycloalkyl, or –C1-6 alkyl–C3-6 cycloalkyl; R8b, R8d, and R8e are each independently H or C1-6 alkyl; PATENT Attorney Docket No.052687-509001WO alternatively R8b and R8d together with the carbon to which each is attached combine to form a C3-6 cycloalkyl; ring B is C6-12 aryl or heteroaryl having 5 to 12 ring members and 1 to 6 heteroatoms, each independently N, O, or S; the subscript m8 is 0, 1, 2, 3, 4, or 5; each R8f is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 deuteroalkoxy, C2-6 alkoxyalkyl, halo, C1-6 haloalkyl, C1-6 haloalkoxy, cyano, –X8f–cyano, –NR8f1R8f2, –C(O)NR8f1R8f2, –N(R8f1)C(O)R8f2, C3-12 cycloalkyl, –X8f–C3-6 cycloalkyl, heterocycloalkyl, –X8f–heterocycloalkyl, C6-12 aryl, –X8f–C 6-12 aryl, heteroaryl, or –X8f–heteroaryl, wherein each heterocycloalkyl has 3 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein each alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R8f3; alternatively, two R8f groups on adjacent ring vertices combine to form a C3-6 cycloalkyl or a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the cycloalkyl or heterocycloalkyl is substituted with 0, 1, 2, or 3 R8f3; each X8f is independently C1-6 alkylene, C2-6 alkenylene, –O–C1-6 alkylene, C(O), O, or S; each R8f1 and R8f2 are independently H or C1-6 alkyl; each R8f3 is independently C1-6 alkyl, –Y8–C1-6 alkyl, C1-6 deuteroalkyl, –Y8–C1-6 deuteroalkyl, –OH, –C1-6 alkyl–OH, –Y8–C1-6 alkyl–OH, –C1-6 alkyl–Y8–C1-6 alkyl, –(C1-2 alkyl–O)1-4–C1-2 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl, –Y8–C1-6 haloalkyl, cyano, –C1-6 alkyl–cyano, –C1-6 alkyl–NR8gR8h, oxo, C3-6 cycloalkyl, –X8f3–C3-6 cycloalkyl, heterocycloalkyl, –X8f3– heterocycloalkyl, phenyl, –X8f3–phenyl, heteroaryl, or –X8f3–heteroaryl, wherein each heterocycloalkyl has 3 to 12 members and 1 to 4 heteroatoms, each independently N, O, S, or S(O)2, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, and wherein each heterocycloalkyl and heteroaryl are substituted with 0, 1, or 2 C1-4 alkyl or halo; alternatively, two R8f3 groups on the same or adjacent ring vertices combine to form a C3-6 cycloalkyl or a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein nitrogen atom ring members in the heterocycloalkyl are substituted with 0 or 1 C1-4 alkyl; PATENT Attorney Docket No.052687-509001WO each X8f3 is independently C1-6 alkylene, O, C(O), or S(O)2; each Y8 is independently C(O), C(O)O, N(R8f4)C(O), O, S, or S(O)2; each R8g and R8h is independently H, C1-6 alkyl, or C1-6 haloalkyl; and each R8f4 is independently H or C1-6 alkyl; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, or the pharmaceutically acceptable salt thereof, wherein R3 is (a) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C1-6 haloalkyl substituted with 0, 1, 2, 3, 4 or 5 R3a. 3. The compound of claim 1, or the pharmaceutically acceptable salt thereof, wherein R3 is (a) C1-6 alkyl or C1-6 haloalkyl substituted with 0, 1, or 2 R3a. 4. The compound of any one of claims 1 to 3, or the pharmaceutically acceptable salt thereof, wherein each R3a is –OH. 5. The compound of claim 1 or 2, or the pharmaceutically acceptable salt thereof, wherein R3 is (b) C3-7 cycloalkyl substituted with 0, 1, 2, or 3 R3b. 6. The compound of claim 1 or 2, or the pharmaceutically acceptable salt thereof, wherein R3 is (b) C3-4 cycloalkyl substituted with 0, 1, or 2 R3b. 7. The compound of claim 5 or claim 6, or the pharmaceutically acceptable salt thereof, wherein each R3b is halo or C1-4 haloalkyl. 8. The compound of claim 1, or the pharmaceutically acceptable salt thereof, wherein R3 is (c) heterocycloalkyl having 3 to 6 ring 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 R3c. 9. The compound of claim 8, or the pharmaceutically acceptable salt thereof, wherein each R3c is halo or C1-4 haloalkyl. 10. The compound of claim 8, or the pharmaceutically acceptable salt thereof, wherein each R3c is fluoro or trifluoromethyl. 11. The compound of any one of claims 1 to 10, or the pharmaceutically acceptable salt thereof, wherein R3 is PATENT Attorney Docket No.052687-509001WO . 12. The 11, or the pharmaceutically acceptable salt thereof, wherein R4a, R4b, and R4c are each independently H or C1-6 alkyl; alternatively, R4c and R4a 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 R4a1; and each R4a1 is independently halo. 13. The compound of any one of claims 1 to 11, or the pharmaceutically acceptable salt thereof, wherein R4a, R4b, and R4c are each independently H or C1-6 alkyl. 14. The compound of any one of claims 1 to 11, or the pharmaceutically acceptable salt thereof, wherein R4b is H or C1-6 alkyl; and R4c and R4a 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 R4a1. 15. The compound of any one of claims 1 to 14, or the pharmaceutically acceptable salt thereof, wherein R4b is H; and R4c and R4a together with the carbon and nitrogen to which each is attached combine to form a pyrrolidinyl, wherein the pyrrolidinyl is substituted with 0 or 1 fluoro. 16. The compound of any one of claims 1 to 15, or the pharmaceutically acceptable salt thereof, wherein X5 is a bond. 17. The compound of any one of claims 1 to 15, or the pharmaceutically acceptable salt thereof, wherein X5 is –C(O)NH. PATENT Attorney Docket No.052687-509001WO 18. The compound of any one of claims 1 to 17, or the pharmaceutically acceptable salt thereof, wherein ring C is 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, or 4 R5e. 19. The compound of any one of claims 1 to 17, or the pharmaceutically acceptable salt thereof, wherein ring C is heteroaryl having 9 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein the heteroaryl is substituted with 0, 1, 2, 3, or 4 R5e. 20. The compound of any one of claims 1 to 19, or the pharmaceutically acceptable salt thereof, wherein R5e is independently C1-6 alkyl, –OH, halo, or oxo. 21. The compound of any one of claims 1 to 19, or the pharmaceutically acceptable salt thereof, wherein R5e is independently C1-6 alkyl, –OH, or halo. 22. The compound of any one of claims 1 to 21, or the pharmaceutically acceptable salt thereof, wherein ring C is . acceptable salt thereof, wherein R6b and R6d are each independently H or C1-6 alkyl. 24. The compound of any one of claims 1 to 23, or the pharmaceutically acceptable salt thereof, wherein R6b is H; and R6d is H or methyl. 25. The compound of any one of claims 1 to 24, or the pharmaceutically acceptable salt thereof, wherein X6 is C6-7 alkylene. 26. The compound of any one of claims 1 to 24, or the pharmaceutically acceptable salt thereof, wherein X6 is C6-7 alkenylene. PATENT Attorney Docket No.052687-509001WO 27. The compound of any one of claims 1 to 26, or the pharmaceutically acceptable salt thereof, wherein X6 is . 28. The 1 to 26, or the pharmaceutically acceptable salt thereof, wherein X6 is , wherein the wavy bond attached to E, Z, or a mixture of both isomers. 29. The compound of any one of claims 1 to 28, or the pharmaceutically acceptable salt thereof, wherein R7a and R7b are each independently H or C1-6 alkyl; and R7c is C1-6 alkyl. 30. The compound of any one of claims 1 to 28, or the pharmaceutically acceptable salt thereof, wherein R7a and R7b are each H; and R7c is C1-6 alkyl. 31. The compound of any one of claims 1 to 30, or the pharmaceutically acceptable salt thereof, wherein R7a and R7b are each H; and R7c is isobutyl. 32. The compound of any one of claims 1 to 31, or the pharmaceutically acceptable salt thereof, wherein R8a, R8b, R8d, and R8e are each independently H or C1-6 alkyl. PATENT Attorney Docket No.052687-509001WO 33. The compound of any one of claims 1 to 31, or the pharmaceutically acceptable salt thereof, wherein R8a is methyl; and R8b, R8d and R8e are each H. 34. The compound of any one of claims 1 to 33, or the pharmaceutically acceptable salt thereof, wherein ring B is phenyl. 35. The compound of any one of claims 1 to 33, or the pharmaceutically acceptable salt thereof, wherein ring B is biphenyl. 36. The compound of any one of claims 1 to 33, or the pharmaceutically acceptable salt thereof, wherein ring B is a heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, wherein each heteroatom is N. 37. The compound of any one of claims 1 to 33, or the pharmaceutically acceptable salt thereof, wherein ring B is pyridyl. 38. The compound of any one of claims 1 to 37, or the pharmaceutically acceptable salt thereof, wherein the subscript m8 is 1, 2, or 3. 39. The compound of any one of claims 1 to 37, or the pharmaceutically acceptable salt thereof, wherein the subscript m8 is 2. 40. The compound of any one of claims 1 to 39, or the pharmaceutically acceptable salt thereof, wherein at least one R8f is halo. 41. The compound of any one of claims 1 to 40, or the pharmaceutically acceptable salt thereof, wherein each R8f is independently C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C1-6 deuteroalkoxy, halo, C1-6 haloalkyl, cyano, or –X8f–cyano. 42. The compound of any one of claims 1 to 40, or the pharmaceutically acceptable salt thereof, wherein each R8f is independently halo, C3-6 cycloalkyl, –X8f–C3-6 cycloalkyl, –CH=CR8f5R8f6, heterocycloalkyl, –X8f–heterocycloalkyl, phenyl, –X8f–phenyl, heteroaryl, or – X8f–heteroaryl, wherein each heterocycloalkyl has 3 to 10 ring members and 1 PATENT Attorney Docket No.052687-509001WO to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is substituted with 0, 1, 2, or 3 R8f3; each X8f is independently C1-6 alkylene, C2-6 alkenylene, O, or S; and each R8f5 and R8f6 are combined with the carbon to which they are attached to form a heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms, each independently N, O or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, or 3 R8f3. 43. The compound of any one of claims 1 to 42, or the pharmaceutically acceptable salt thereof, wherein each X8f is independently C1-6 alkylene. 44. The compound of any one of claims 1 to 40, or the pharmaceutically acceptable salt thereof, wherein each R8f is independently halo, C3-6 cycloalkyl, –CH=CR8f5R8f6, heterocycloalkyl, phenyl, or heteroaryl, wherein each heterocycloalkyl has 3 to 10 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is substituted with 0, 1, 2, or 3 R8f3; each R8f5 and R8f6 are combined with the carbon to which they are attached to form a heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms, each independently N, O or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, or 3 R8f3. 45. The compound of any one of claims 1 to 40, or the pharmaceutically acceptable salt thereof, wherein each R8f is independently C1-4 alkyl, C2-4 alkenyl, C1-4 alkoxy, C1-4 deuteroalkoxy, halo, C1-4 haloalkyl, cyano, or –C1-2 alkyl–cyano. 46. The compound of any one of claims 1 to 40, or the pharmaceutically acceptable salt thereof, wherein each R8f is independently halo, C3-6 cycloalkyl, –O–C3-6 cycloalkyl, heterocycloalkyl, –C2-4 alkenyl–heterocycloalkyl, –O–heterocycloalkyl, phenyl, –O–phenyl, PATENT Attorney Docket No.052687-509001WO heteroaryl, or –O–heteroaryl, wherein each 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, heterocycloalkyl, phenyl, and heteroaryl is substituted with 0, 1, 2, or 3 R8f3. 47. The compound of any one of claims 1 to 40, or the pharmaceutically acceptable salt thereof, wherein each R8f is independently halo, C3-6 cycloalkyl, –O–C3-6 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 R8f3. 48. The compound of any one of claims 1 to 40, or the pharmaceutically acceptable salt thereof, wherein each R8f is independently halo, heterocycloalkyl, –O–heterocycloalkyl, phenyl, or –O–phenyl, wherein each heterocycloalkyl 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 R8f3. 49. The compound of any one of claims 1 to 48, or the pharmaceutically acceptable salt thereof, wherein each R8f3 is independently C1-6 alkyl, –Y8–C1-6 alkyl, C1-6 deuteroalky, –Y8–C1-6 deuteroalkyl, –OH, –C1-6 alkyl–OH, –Y8–C1-6 alkyl–OH, –C1-6 alkyl–Y8–C1-6 alkyl, halo, C1-6 haloalkyl, –Y8–C1-6 haloalkyl, or oxo; each Y8 is independently C(O), C(O)O, N(R8f4)C(O), O, S, or S(O)2; and each R8f4 is independently H or C1-6 alkyl. 50. The compound of any one of claims 1 to 48, or the pharmaceutically acceptable salt thereof, wherein each R8f3 is independently C1-6 alkyl, C1-6 deuteroalky, –OH, –C1-6 alkyl–OH, halo, C1-6 haloalkyl, or oxo. 51. The compound of any one of claims 1 to 48, or the pharmaceutically acceptable salt thereof, wherein each R8f3 is independently C1-6 alkyl or –Y8–C1-6 alkyl. PATENT Attorney Docket No.052687-509001WO 52. The compound of any one of claims 1 to 51, or the pharmaceutically acceptable salt thereof, wherein each Y8 is independently a C(O) or C(O)O. 53. The compound of any one of claims 1 to 48, or the pharmaceutically acceptable salt thereof, wherein each R8f3 is independently C3-6 cycloalkyl, –X8f3–C3-6 cycloalkyl, heterocycloalkyl, or –X8f3–heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 members and 1 to 2 heteroatoms, each independently N, O, S, or S(O)2; and each X8f3 is independently C1-6 alkylene, C(O), or S(O)2. 54. The compound of any one of claims 1 to 53, or the pharmaceutically acceptable salt thereof, wherein each R8f3 is independently C3-6 cycloalkyl or heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 members and 1 to 2 heteroatoms, each independently N, O, S, or S(O)2. 55. The compound of any one of claims 1 to 53, or the pharmaceutically acceptable salt thereof, wherein each X8f3 is independently C1-6 alkylene. 56. The compound of any one of claims 1 to 55, or the pharmaceutically acceptable salt thereof, wherein two R8f3 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. 57. The compound of any one of claims 1 to 48, or the pharmaceutically acceptable salt thereof, wherein each R8f3 is independently C1-4 alkyl, C1-4 alkoxy, C2-6 alkoxyalkyl, –S(O)2–C1-4 alkyl, –C1-4 alkyl–S(O)2–C1-4 alkyl, halo, C1-4 haloalkyl, oxo, –C(O)–C1-4 alkyl, or –C(O)O–C1-4 alkyl. 58. The compound of any one of claims 1 to 57, or the pharmaceutically acceptable salt thereof, wherein m8 is 2; and PATENT Attorney Docket No.052687-509001WO each R8f is independently fluoro, chloro, bromo, , thereof, wherein R3 is ; R4b is R4c and R4a together with the carbon and nitrogen to which each is attached combine to form a pyrrolidinyl, wherein the pyrrolidinyl is substituted with 0 or 1 fluoro; X5 is a bond or –C(O)NH–; ring C is ; X6 is ; R6b is R6d is H or methyl; PATENT Attorney Docket No.052687-509001WO R7a is H; R7b is H; R7c is isobutyl; R8a is methyl; R8b, R8d and R8e are each H; ring B is phenyl, biphenyl, or pyridyl; m8 is 2; and each R8f is independently fluoro, chloro, bromo, , acceptable salt thereof, having the compound of Formula (Ia): . or salt thereof, having the structure of any one of Examples 1-36. 62. A pharmaceutical composition comprising a compound of any one of claims 1 to 61 and a pharmaceutically acceptable excipient. PATENT Attorney Docket No.052687-509001WO 63. A method of treating a cancer mediated at least in part by cyclin A comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 62, thereby treating the disorder or condition. 64. A compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 62 for use in a method for treating a cancer mediated at least in part by cyclin A. 65. Use of a compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 62 for the manufacture of a medicament for the treatment of a cancer mediated at least in part by cyclin A.
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