WO2025034883A1 - Combination therapies with kras modulators - Google Patents

Combination therapies with kras modulators Download PDF

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Publication number
WO2025034883A1
WO2025034883A1 PCT/US2024/041318 US2024041318W WO2025034883A1 WO 2025034883 A1 WO2025034883 A1 WO 2025034883A1 US 2024041318 W US2024041318 W US 2024041318W WO 2025034883 A1 WO2025034883 A1 WO 2025034883A1
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alkyl
heterocycle
optionally substituted
carbocycle
halogen
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PCT/US2024/041318
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French (fr)
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Hong Lin
Cameron PITT
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Quanta Therapeutics, Inc.
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Publication of WO2025034883A1 publication Critical patent/WO2025034883A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • KRAS mutations drive approximately 25% of human cancers by aberrant regulation of the mitogen-activated protein kinase (MAPK) signaling cascade and other effector pathways (e.g., see Stephen, A.G., et al., Dragging ras back in the ring. Cancer Cell, 2014.25(3): p.272-81).
  • MPK mitogen-activated protein kinase
  • Ras has been recognized as a target in cancer for about 40 years, Ras-driven cancers remain among the most difficult to treat due to insensitivity to available targeted therapies.
  • Ras encoded by the three major genes KRAS, NRAS and HRAS, has the highest frequency of mutation of any oncogene. All oncogenic Ras mutations drive the switch to accumulate in the active GTP-bound state.
  • Ras mutations in codon 12 impair the small GTPases’ ability to perform their role in hydrolyzing GTP. This regulatory impairment is fundamental for initiating and maintaining tumor progression.
  • GAP GTPase activating protein
  • SOS guanine nucleotide exchange factor
  • KRAS G12C mutations most common in lung adenocarcinoma, have been clinically shown to be susceptible to direct inhibition by covalent modification with small molecule inhibitors trapping the protein in the inactive GDP-bound state.
  • KRAS G12D mutation confers a significantly slower intrinsic rate of GTP hydrolysis than G12C, resulting in more constitutive activation.
  • pharmacological targeting the of inactive state is unlikely to achieve similar results against G12D, despite the existence of a similar binding pocket in the GDP-state.
  • a cysteine present at the site of the activating mutation yields itself to covalent chemistry, while aspartic acid does not provide typical medicinal chemistry approaches for selective covalent modification.
  • KRAS- mutant-selective inhibition in this pathway is considered the critical functional readout for potential clinical benefit of novel therapeutic approaches.
  • oncogenic KRas mutations create an immunosuppressive microenvironment which can result in resistance to immune checkpoint blockade (ICB) therapy, including anti-PD-1 and anti-PD-L1 inhibitors.
  • ICB immune checkpoint blockade
  • Activated KRas has been demonstrated to repress the expression of interferon regulatory factor 2 (IRF2), which directly represses CXCL3 expression.
  • IRF2 interferon regulatory factor 2
  • KRas-mediated repression of IRF2 leads to increased expression of CXCL3, which binds to CXCR2 on myeloid-derived suppressor cells (MDSC) promoting migration of these cells to the tumor microenvironment.
  • MDSC myeloid-derived suppressor cells
  • a role for KRas in modulating the immune microenvironment and primary ICB resistance in advanced colorectal cancer has been established.
  • anti-PD-1 resistance of KRAS-expressing tumors can be overcome by enforced IRF2 expression or by inhibition of CXCR2. (e.g., see Liao et al., (2019) Cancer Cell 35:559 - 572).
  • oncogenic KRas signaling has been shown to promote tumor immunoresistance to ICB therapy by stabilizing PD-L1 mRNA via repression of the AU- rich element-binding protein tristetraprolin (TTP), which negatively regulates PD-L1 expression through AU-rich elements in the 3' UTR of PD-L1 mRNA (e.g., see Coelho et al., (2017) Immunity 47(6): 1083-1099).
  • TTP AU- rich element-binding protein tristetraprolin
  • KRas activating mutations upregulate IL-8 expression in NSCLC
  • IL-8 plays a role in cell growth and migration in KRas-associated NSCLC (e.g., see Sunaga et al., (2012) Int. J. Cancer 130(8):1733-1744).
  • activated KRas mutations or other KRas-activating generic alterations expression may modulate many aspects of the immune system and can be responsible for the immunosuppressive tumor microenvironment in KRas mutant or hyperactivated Kras wildtype- associated tumors.
  • the direct inhibition of KRas mutant or hyperactivated Kras wildtype-associated-mediated cell activity may reverse this reported immunosuppressive tumor microenvironment thereby improving the clinical activity of immune checkpoint blockade therapy, including the PD-1/PD-L1 pathway.
  • compounds described herein may reprogram the tumor microenvironment (TME) in favor of antitumor immunity, by modulating tumor cell cytokine/chemokine release. Specifically, treatment with compounds described herein reduces immunosuppressive cytokine release while increasing immunostimulatory chemokine release in KRAS mutant cells.
  • TEE tumor microenvironment
  • results of our study herein reveal a direct mechanism by which compounds described herein can modify tumor-cell-intrinsic immune signals to enhance antitumor immunity in a synergistic manner with the use of common immune checkpoint inhibitors.
  • the present disclosure provides combination therapies useful for treating a disease or disorder (e.g., cancer).
  • a disease or disorder e.g., cancer
  • an agent that disrupts Programmed cell death protein 1 (PD-1) and Programmed death-ligand 1 (PD-L1) axis signaling e.g., a PD-1 inhibitor, a PD-L1 inhibitor
  • kits comprising the compositions and methods of use therefor.
  • FIG.1 illustrates that compounds herein reduce immunosuppressive cytokine release while increasing immunostimulatory chemokine release in KRAS-mutant HPAC cells.
  • DETAILED DESCRIPTION OF THE INVENTION [0019] The following description sets forth numerous exemplary configurations, methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to fifteen carbon atoms (i.e., C 1 -C 15 alkyl).
  • an alkyl comprises one to thirteen carbon atoms (i.e., C 1 -C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C 1 -C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C 1 -C 5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C 1 -C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C 1 -C 3 alkyl).
  • an alkyl comprises one to two carbon atoms (i.e., C 1 -C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C 1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C 5 -C 15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C 3 -C 5 alkyl).
  • the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl).
  • the alkyl is attached to the rest of the molecule by a single bond.
  • the term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
  • C 1-6 alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons.
  • the term –Cx-yalkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain.
  • –C 1-6 alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.
  • Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-C6 alkenyl).
  • an alkenyl comprises two to four carbon atoms (i.e., C 2 -C 4 alkenyl).
  • the alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkynyl).
  • an alkynyl comprises two to eight carbon atoms (i.e., C2-C8 alkynyl).
  • an alkynyl comprises two to six carbon atoms (i.e., C 2 -C 6 alkynyl).
  • an alkynyl comprises two to four carbon atoms (i.e., C 2 -C 4 alkynyl).
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • C x-y alkenyl and C x-y alkynyl refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • the term –Cx-yalkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain.
  • –C 2-6 alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted.
  • An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain.
  • the term –Cx-yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkenylene chain.
  • alkenylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted.
  • An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.
  • "Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain.
  • an alkylene comprises one to ten carbon atoms (i.e., C 1 -C 8 alkylene).
  • an alkylene comprises one to eight carbon atoms (i.e., C 1 -C8 alkylene).
  • an alkylene comprises one to five carbon atoms (i.e., C 1 -C5 alkylene).
  • an alkylene comprises one to four carbon atoms (i.e., C 1 -C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C 1 -C 3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C 1 -C 2 alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., C1 alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., C5-C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C 2 -C 5 alkylene).
  • an alkylene comprises three to five carbon atoms (i.e., C3-C5 alkylene).
  • "Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain.
  • an alkenylene comprises two to ten carbon atoms (i.e., C2-C10 alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C 2 -C 8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C 2 -C 4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C 2 -C 3 alkenylene).
  • an alkenylene comprises two carbon atom (i.e., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C 3 -C 5 alkenylene).
  • Alkynylene or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms.
  • an alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkynylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain.
  • an alkynylene comprises two to ten carbon atoms (i.e., C2-C10 alkynylene).
  • an alkynylene comprises two to eight carbon atoms (i.e., C2-C8 alkynylene).
  • an alkynylene comprises two to five carbon atoms (i.e., C 2 -C 5 alkynylene).
  • an alkynylene comprises two to four carbon atoms (i.e., C 2 -C 4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C 5 -C 8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C 3 -C 5 alkynylene).
  • Aryl refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • Alkyl refers to a radical of the formula -R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • Alkenyl refers to a radical of the formula –R d -aryl where R d is an alkenylene chain as defined above.
  • Alkynyl refers to a radical of the formula -R e -aryl, where R e is an alkynylene chain as defined above.
  • Carbocycle refers to a saturated, unsaturated or aromatic rings in which each atom of the ring is carbon.
  • Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, and 6- to 12-membered bridged rings.
  • Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings.
  • An aromatic ring e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic.
  • Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl.
  • Bicyclic carbocycles may be fused, bridged or spiro-ring systems. In some cases, spiro-ring carbocycles have at least two molecular rings with only one common atom.
  • unsaturated carbocycle refers to carbocycles with at least one degree of unsaturation and excluding aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene.
  • Cycloalkyl refers to a fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond.
  • Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • Cycloalkenyl refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond.
  • a cycloalkenyl comprises three to ten carbon atoms.
  • a cycloalkenyl comprises five to seven carbon atoms.
  • the cycloalkenyl may be attached to the rest of the molecule by a single bond.
  • Examples of monocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Cycloalkylalkyl refers to a radical of the formula –R c -cycloalkyl where R c is an alkylene chain as described above.
  • Cycloalkylalkoxy refers to a radical bonded through an oxygen atom of the formula – O-R c -cycloalkyl where R c is an alkylene chain as described above.
  • Halo or “halogen” refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.
  • haloalkyl or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally further substituted.
  • haloalkanes examples include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2- haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.).
  • halogen substituted alkanes e.g., Cl, Br, F, I, etc.
  • each halogen may be independently selected e.g., 1-chloro,2-fluoroethane.
  • fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amine radicals, for example, propan-2-amine, butane-1,2-diamine, pentane-1,2,4-triamine and the like.
  • Hydroxyalkyl refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, for example, propan-1-ol, butane-1,4-diol, pentane-1,2,4-triol, and the like.
  • Alkoxyalkyl refers to an alkyl radical, as defined above, that is substituted by one or more alkoxy radicals, for example, methoxymethane, 1,3-dimethoxybutane, 1-methoxypropane, 2-ethoxypentane, and the like.
  • Cyanoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more cyano radicals, for example, acetonitrile, 2-ethyl-3- methylsuccinonitrile, butyronitrile, and the like.
  • Heterocycle refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms.
  • exemplary heteroatoms include N, O, Si, P, B, and S atoms.
  • the heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle.
  • Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings.
  • a bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits.
  • an aromatic ring e.g., pyridyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene.
  • a bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5- 6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems.
  • Bicyclic heterocycles may be fused, bridged, or spiro-ring systems.
  • a spiro-ring system may be referred as a “spiroheterocycle”, “spiro heterocycle”, or “spiro-heterocycle”.
  • spiro-heterocycles, spiro heterocycles, or spiroheterocycles have at least two molecular rings with only one common atom.
  • the spiro- heterocycle, spiro heterocycle, or spiroheterocycle comprises one or more heteroatoms.
  • Heterocyclene refers to a divalent heterocycle linking the rest of the molecule to a radical group.
  • Heteroaryl or “aromatic heterocycle” refers to a radical derived from a heteroaromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S.
  • the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ – electron system in accordance with the Hückel theory.
  • the heteroatom(s) in the heteroaryl radical may be optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • the heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl.
  • heteroaryls include, but are not limited to, pyridine, pyrimidine, oxazole, furan, pyran, thiophene, isoxazole, benzimidazole, benzthiazole, and imidazopyridine.
  • An “X-membered heteroaryl” refers to the number of endocylic atoms, i.e., X, in the ring.
  • a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.
  • the term “unsaturated heterocycle” refers to heterocycles with at least one degree of unsaturation and excluding aromatic heterocycles. Examples of unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine. Heterocycles may be optionally substituted by one or more substituents such as those substituents described herein.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • electrophile or “electrophilic moiety” is any moiety capable of reacting with a nucleophile (e.g., a moiety having a lone pair of electrons, a negative charge, a partial negative charge and/or an excess of electrons, for example an —SH group).
  • Electrophiles typically are electron poor or comprise atoms which are electron poor.
  • an electrophile contains a positive charge or partial positive charge, has a resonance structure which contains a positive charge or partial positive charge, or is a moiety in which delocalization or polarization of electrons results in one or more atoms which contains a positive charge or partial positive charge.
  • an electrophile comprises a conjugated double bond, for example an ⁇ , ⁇ -unsaturated carbonyl or ⁇ , ⁇ -unsaturated thiocarbonyl compound.
  • the term “optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.
  • the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.
  • salt or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable excipient or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • the terms “treat,” “treating” or “treatment,” as used herein, may include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • G12 mutants refers to other oncogenic alleles of KRAS at amino acid position 12 (ie. G12X).
  • KRas G12D-associated cancer refers to cancers associated with or mediated by or having a KRas G12D mutation.
  • KRas G12V-associated cancer refers to cancers associated with or mediated by or having a KRas G12V mutation.
  • KRas wildtype-associated cancer refers to cancers associated with or mediated by or having a KRas wildtype.
  • immunomodulator inhibitor refers to an agent that modifies, or modulates, the immune system to help a subject respond to a disease or disorder.
  • PD-1 inhibitor refers to an agent that is capable of negatively modulating or inhibiting all or a portion of the PD-1 axis signaling activity and include agents that block PD-1.
  • PD-L1 inhibitor refers to an agent that is capable of negatively modulating or inhibiting all or a portion of the PD-L1 axis signaling activity and include agents that block PD-L1.
  • PD-1 binding antagonist is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and/or PD-L2.
  • PD-L1 binding antagonist is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-1 and/or B7-1.
  • biosimilar means an antibody or antigen-binding fragment that has the same primary amino acid sequence as compared to a reference antibody (e.g., nivolumab or pembrolizumab) and optionally, may have detectable differences in post-translation modifications (e.g., glycosylation and/or phosphorylation) as compared to the reference antibody (e.g., a different glycoform).
  • the terms "subject,” “individual,” and “patient” may be used interchangeably and refer to humans, as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like).
  • the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context.
  • the subject may not be under the care or prescription of a physician or other health worker.
  • a subject in need thereof refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.
  • the terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of” can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.
  • administer are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration.
  • oral routes of administering a composition can be used.
  • administer should be understood to mean providing a compound of the disclosure or a prodrug of a compound of the disclosure to the individual in need.
  • the term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or salt described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below.
  • the therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term can also apply to a dose that can induce a particular response in target cells, e.g., reduction of proliferation or down regulation of activity of a target protein.
  • a "therapeutically effective amount of a combination" of two compounds is an amount that together synergistically increases the activity of the combination in comparison to the therapeutically effective amount of each compound in the combination, i.e., more than merely additive.
  • “synergy,” “synergetic,” “synergism,” or “synergistic effect” refer to two or more compounds or compositions, that individually produce an effect, however, together produce a combined effect that is greater than their individual effects.
  • the term “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art.
  • “about” can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value.
  • any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.
  • COMPOSITIONS AND INHIBITORS Immunomodulator Inhibitors [0084] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a combination of: i) an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • Formula (II) is represented by Formula (II*).
  • the immunomodulator inhibitor is selected from a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor. In some cases, the immunomodulator inhibitor is a PD-1 inhibitor.
  • the immunomodulator inhibitor is a PD-L1 inhibitor. In some cases, the immunomodulator inhibitor is a CTLA-4 inhibitor. [0088] In some embodiments, the immunomodulator inhibitor is selected from a PD-1/PD-L1 checkpoint inhibitor. [0089] In some embodiments, the immunomodulator inhibitor is immune checkpoint inhibitor. [0090] In some embodiments, the immunomodulator inhibitor is pembrolizumab. [0091] In some embodiments, the immunomodulator inhibitor is relatlimab. PD-1/PD-L1 Inhibitors [0092] In some embodiments, programmed death protein 1 (PD-1) is an immunoinhibitory receptor that is primarily expressed on activated T and B cells.
  • PD-1 programmed death protein 1
  • PD-1 is a 55 kDa type I transmembrane protein that is part of the Ig gene superfamily (Agata et al. (1996) Int Immunol 8:765-72).
  • PD-1 contains a membrane proximal immunoreceptor tyrosine inhibitory motif (ITIM) and a membrane distal tyrosine-based switch motif (ITSM).
  • ITIM immunoreceptor tyrosine inhibitory motif
  • ITSM membrane distal tyrosine-based switch motif
  • Two ligands that bind to PD-1 have been identified, PD-L1 and PD-L2, that have been shown to downregulate T cell activation upon binding to PD-1 (Freeman et al. (2000) J Exp Med 192: 1027-34).
  • PD-L1 is a ligand for PD-1 and is abundant in a variety of human cancers (Dong et al. (2002) Nat. Med.8:787-9). In some cases, the interaction between PD-1 and PD-L1 results in a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and immune evasion by the cancerous cells (Dong et al. (2003) J. Mol. Med.81:281-7). [0093] In some embodiments, immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-Ll, and the effect is additive when the interaction of PD-1 with PD- L2 is blocked as well.
  • PD-L1 is upregulated in many cancers and contributes to evasion of the host immune system, blocking the interaction between PD-1 and PD-L1 has garnered the attention of the pharmaceutical industry leading to a new break-through class of immune checkpoint therapies for a wide range of cancers.
  • the PD-1/PD-L1 pathway is a well-validated target for the development of antibody therapeutics for cancer treatment and several anti-PD-1 and anti-PD-L1 antibodies have undergone human clinical trials for a wide-variety of cancers including NSCLC, renal cell carcinoma, melanoma, head and neck squamous cancer, ureothelial cancer, hepatocellular carcinoma, and other cancers.
  • anti-PD-1 antibodies include nivolumab (Opdivo®), pembrolizumab (Keytruda®), cemiplimab (Libtayo®) and tislelizumab, and biosimilars thereof.
  • anti-PD-L1 antibodies include atezolizumab (Tecentriq®), avelumab (Bavencio®), and durvalumab (Imfinzi®), and biosimilars thereof.
  • methods for manufacturing agents that disrupt PD-1/PD-L1 signaling axis including the antibodies described herein, are well known to those skilled in the art and agents that disrupt PD-1/PD-L1 signaling axis may be obtained from a wide-variety of commercial suppliers, in forms suitable for both research or approved human clinical use.
  • suitable agents that disrupt PD-1/PD-L1 signaling for use in the compositions and methods disclosed herein and methods for preparing such agents, and diagnostic and efficacy markers useful for monitoring treatment are disclosed in US Patent Application Publication Nos: 20180327848; 20180237524; 20180148790; 20180111996; 20160305947; 20160304969; 20160304606; 20150232555; 20150079109; 20140348743; 20140294852; 20140271684; 20140234296; 20130133091; 20110123550; and 20090217401.
  • PD-1 inhibitor [0096]
  • methods of treating a disease or disorder in a subject in need thereof comprising administering to the subject a combination of: i) an PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) an PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • methods of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • Formula (II) is represented by Formula (II*).
  • a PD-1 inhibitor is selected from a PD-1 binding antagonist.
  • the PD-1 binding antagonist is selected from anti-PD-1 antibodies, antigen binding fragments thereof, immunoadhesins, aptamers, fusion proteins, and oligopeptides.
  • the PD-1 binding antagonist is an anti-PD-1 antibody.
  • the PD-1 inhibitor is a molecule that inhibits the binding of PD-1 to its binding partners. In some cases, the PD-1 inhibitor inhibits the binding of PD-1 to PD-L1 and/or PD-L2.
  • PD-1 inhibitors include anti-PD-1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and/or PD-L2.
  • a PD-1 inhibitor reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T-cell less non- dysfunctional.
  • the PD-1 inhibitor is an anti-PD-1 antibody.
  • the PD- 1 antibody is pembrolizumab, or a biosimilar thereof.
  • the PD-1 antibody is cemiplimab, or a biosimilar thereof. In some cases, the PD-1 antibody is tislelizumab, or a biosimilar thereof.
  • PD-L1 Inhibitors [00102] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a combination of: i) an PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • kits for treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • a PD-L1 inhibitor is selected from a PD-L1 binding antagonist.
  • the PD-L1 binding antagonist is selected from an anti-PD-L1 antibody, antigen binding fragments thereof, immunoadhesins, aptamers, fusion proteins, and oligopeptides. In some cases, the PD-L1 binding antagonist is an anti-PD-L1 antibody.
  • a PD-L1 inhibitor is a molecule that inhibits the binding of PD- L1 to its binding partners. In some cases, the PD-L1 inhibitor inhibits binding of PD-L1 to PD-1 and/or B7-1.
  • the PD-L1 inhibitors include anti-PD-L1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and/or B7-1.
  • a PD-L1 inhibitor reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L1 so as render a dysfunctional T-cell less non-dysfunctional.
  • a PD-L1 inhibitor is an anti-PD-L1 antibody.
  • an anti- PD-L1 antibody is avelumab or a biosimilar thereof. In some cases, an anti-PD-L1 antibody is atezolizumab or a biosimilar thereof. In some cases, an anti-PD- L1 antibody is durvalumab or a biosimilar thereof. In some cases, an anti-PD-L1 antibody is BMS-936559 (MDX-1105) or a biosimilar thereof.
  • CTLA-4 inhibitor [00108]
  • methods of treating a disease or disorder in a subject in need thereof comprising administering to the subject a combination of: i) an CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • kits for treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an CTLA-4 inhibitor, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.
  • Formula (II) is represented by Formula (II*).
  • the CTLA-4 inhibitor is selected from lpilimumab.
  • KRAS Inhibitors [00113] The following is a discussion of compounds and salts thereof that may be used in the methods of the disclosure.
  • the compounds and salts may be used in combination with at least one other inhibitor (e.g., immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor).
  • the compounds and salts e.g., a compound of Formula (I), Formula (II), Formula (II*), or Formula (III)
  • may be used in combination with one other inhibitor e.g., immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor.
  • a compound of Formula (I), Formula (II), Formula (III), or sub Formulas thereof may be used in the methods of the disclosure.
  • a compound of Formula (I), Formula (II), Formula (III), or sub Formulas thereof may be referred to as a KRAS inhibitor.
  • a compound of Formula (I), Formula (II), Formula (III), or Formula (II*) may be referred to as a KRAS inhibitor.
  • Formula (I) is represented by Formula (II), Formula (II*), or Formula (III).
  • Ring A is selected from a heterocycle wherein the heterocycle is optionally substituted with one or more substituents selected from R 4 .
  • Ring A includes at least one heteroatom selected from nitrogen, sulfur, and oxygen.
  • the heteroatom of Ring A is nitrogen, wherein the nitrogen is optionally substituted with R 3 , wherein R 3 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, wherein C 3-12 carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO 2 , -NH 2 , -N(C 1-6 alkyl) 2 , C 1-10 alkyl, -C 1-10 haloalkyl, -O-C 1-10 alkyl, oxo, C 3-12 carbocycle, and 3- to 12-member
  • the heteroatom of Ring A is sulfur, wherein the sulfur is optionally substituted with 1 or 2 oxygen atoms. In some cases, the heteroatom of Ring A is oxygen.
  • Ring A is selected from a carbocycle, wherein the carbocycle is optionally substituted with one or more substituents selected from R 4 .
  • R 2 is selected from -L- NR 21 S(O) 2 (R 21 ) and -L-S(O) 2 N(R 21 ) 2 .
  • R 2 is selected from -L- N(R 21 )C(O)(OR 21 ), and -L-OC(O)N(R 21 ) 2 .
  • each R 21 is independently selected from hydrogen; C 1-6 alkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO 2 , -NH 2 , -N(C 1-6 alkyl) 2 , C 1-10 alkyl, -C 1-10 haloalkyl, -O-C 1-10 alkyl, and oxo.
  • each R 21 is independently selected from hydrogen; C 1-6 alkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R 21 is independently selected from hydrogen and C 1-6 alkyl.
  • R 2 is selected from L- bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R 6 .
  • R 2 is selected from L- pyrrolizine, wherein the pyrrolizine is optionally substituted with one or more R 6 .
  • the optional substituents of L are selected from C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkyl, C 3 -C 6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle or 3- to 8-membered heterocycle wherein the C 3 -C 6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen and C 1-6 haloalkyl.
  • each L is independently selected from a substituted C 1 -C 4 alkylene, wherein two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle.
  • each L is independently selected from a substituted C 1 -C 4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle.
  • each L is independently selected from a substituted C3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C 3 carbocycle.
  • each L is independently selected from .
  • R 2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R 6 .
  • the heterocycle is a saturated heterocycle. In some cases, the heterocycle has at least one nitrogen atom and at least one sulfur atom. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom. [00127] In some embodiments, for a compound or salt of Formula (I), R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 . [00128] In some embodiments, for a compound or salt of Formula (I), Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from and , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • R 2 is selected from -L- saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R 6 , and contains one nitrogen atom and one sulfur atom. the heterocycle portion is optionally substituted with one or more R 6 .
  • each R 6 is independently selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, -CN, C 1 -C 3 aminoalkyl, -Q-phenyl, -Q-phenylSO 2 F, -NHC(O)phenyl, -NHC(O)phenylSO 2 F, C 1 -C 3 alkyl substituted pyrazolyl, -N(R 5 ) 2 , (C 1 -C 3 alkoxy)C 1 -C 3
  • each R 6 is independently selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, -CN, and C 1 -C 3 aminoalkyl.
  • each R 6 is independently selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, -N(R 5 ) 2 , and oxo.
  • each R 6 is independently selected from -OH, Cl- C3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 alkoxy, and -N(R 5 ) 2 .
  • each R 6 is independently selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and -N(R 5 ) 2 .
  • R 6 is selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, -CN, and C 1 -C 3 aminoalkyl.
  • R 6 is selected from halogen and C 1 -C 3 alkyl.
  • R 6 is halogen.
  • R 6 is C 1 -C 3 alkyl.
  • R 6 is selected from halogen and C 1 -C 3 alkyl. In some cases, R 6 is selected from methyl and fluorine.
  • R 2 is selected from [00137]
  • Y-R 2 is selected from [00138]
  • Y-R 2 is selected from [00139]
  • Y-R 2 is selected from , and .
  • B is an optionally substituted 5- to 15-membered heterocycle or optionally substituted C3-C15 carbocycle. In some cases, B is an optionally substituted 5- to 15-membered heterocycle. In some cases, B is an optionally substituted C 3 -C 15 carbocycle. [00142] In some embodiments, for a compound or salt of Formula (I), B is an optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle.
  • B is an optionally substituted C8-C15 fused carbocycle.
  • the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C 8 -C 15 fused carbocycle are each bicyclic or tricyclic.
  • the optionally substituted 8- to 15- membered fused heterocycle are each bicyclic or tricyclic.
  • the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle are each bicyclic or tricyclic.
  • B the heterocycle or carbocycle are each independently bicyclic. In some cases, the heterocycle is bicyclic. In some cases, the carbocycle is bicyclic. [00145] In some embodiments, for a compound or salt of Formula (I), B the heterocycle or carbocycle are each independently tricyclic. In some cases, the heterocycle is tricyclic. In some cases, the carbocycle is tricyclic.
  • the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from , each of which is optionally substituted with one or more substituents.
  • the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C 8 -C 15 fused carbocycle is selected from , , , , , and , each of which is optionally substituted with one or more substituents.
  • the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from, , and , each of which is optionally substituted with one or more substituents.
  • the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from oxo, -NH 2 , -CN, halogen, C 1 -C 3 alkyl.
  • the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH 2 , halogen, C 1 -C 3 alkyl.
  • B is selected from .
  • the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH 2 , CN, halogen, C 1 -C 3 alkyl.
  • B is selected from [00153]
  • each R 4 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, hydroxyl, halogen. Ins some cases, each R 4 is independently selected from C 1-6 alkyl, oxo, and halogen.
  • n is selected from 1 and 2. In some cases, n is 0.
  • Y is O.
  • R 1 is selected from optionally substituted 5- to 12-membered heterocycle.
  • R 1 is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR 20 ) 2 , -OR 20 , SR 20 , - S(O) 2 (R 20 ), -S(O) 2 N(R 20 ) 2 , -NR 20 S(O) 2 R 20 , C(O)N(R 20 ) 2 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 ) 2 , - N(R 20 )C(O)OR 20 , -N(R 20 ) 2 , -C(O)R 20 , C(N(R 20 ) 2 , -C(O)R 20 , C(N(R 20 ) 2 , -C(O)R
  • R 1 is selected from C3- C 12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR 20 ) 2 , -OR 20 , -SR 20 , - S(O) 2 (R 20 ), -C(O)N(R 20 ) 2 , -C(O)NR 20 -OR 20 , -S(O) 2 N(R 20 ) 2 , -NR 20 S(O) 2 R 20, -N(R 20 )C(O)R 20 , - N(R 20 )C(O)N(R 20 ) 2 , N(R 20 )C(O)OR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , OC(O)N(
  • R 1 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R 20 ) 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, and C 1-6 haloalkyl.
  • R 20 of R 1 is selected from hydrogen and C 1 -3 alkyl.
  • the 5- to 12-membered heterocycle of R 1 is an unsaturated heterocycle.
  • the 5- to 12-membered heterocycle of R 1 is a saturated heterocycle.
  • 5- to 12-membered heterocycle of R 1 is a bridged heterocycle.
  • R 1 is selected from [00168]
  • L is selected from C 1 -C4 alkylene.
  • L is selected from unsubstituted C 1 -C 4 alkylene.
  • R 2 is -L-heterocycle, optionally substituted with one or more R 6 , wherein the heterocycle portion is a bicyclic heterocycle.
  • the bicyclic heterocycle contains at least 1 nitrogen atom.
  • the bicyclic heterocycle contains at most 1 nitrogen atom.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • R 6 of R 2 is independently selected at each occurrence from halogen, hydroxy, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, cyano, and C 1 -C 3 aminoalkyl.
  • R 6 of R 2 is independently selected at each occurrence from C 1 -C 3 alkyl and halogen.
  • Y-R 2 is selected from [00176]
  • R 2 is selected from -L- NR 21 S(O) 2 (R 21 ) and -L-S(O) 2 N(R 21 ) 2 .
  • R 2 is selected from -L- N(R 21 )C(O)(OR 21 ), and -L-OC(O)N(R 21 ) 2 .
  • each R 21 is independently selected from hydrogen; C 1-6 alkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO 2 , -NH 2 , -N(C 1-6 alkyl) 2 , C 1-10 alkyl, -C 1-10 haloalkyl, -O- C 1-10 alkyl, and oxo.
  • each R 21 is independently selected from hydrogen; C 1-6 alkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle.
  • each R 21 is independently selected from hydrogen and C 1-6 alkyl.
  • R 3 is selected from hydrogen and C 1-6 alkyl.
  • M is selected from O, NH, and NMe. In some cases, M is O. In some cases, M is selected from NH and NMe.
  • B is an optionally substituted 5- to 15-membered heterocycle or optionally substituted C3-C15 carbocycle. In some cases, B is an optionally substituted 5- to 15-membered heterocycle.
  • B is an optionally substituted C 3 -C 15 carbocycle. In some cases, B is an optionally substituted 8- to 15- membered heterocycle. In some cases, B is an optionally substituted C8-C15 carbocycle. [00183] In some embodiments, for a compound or salt of Formula (II), B is an optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C 8 -C 15 fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted C8-C15 fused carbocycle.
  • the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C 8 -C 15 fused carbocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15- membered fused heterocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C 8 -C 15 fused carbocycle are each bicyclic or tricyclic.
  • the optionally substituted 8- to 15-membered heterocycle contains at least one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least two heteroatoms. [00186] In some embodiments, for a compound or salt of Formula (II), B the heterocycle or carbocycle are each independently bicyclic.
  • the heterocycle is bicyclic. In some cases, the carbocycle is bicyclic. [00187] In some embodiments, for a compound or salt of Formula (II), B the heterocycle or carbocycle are each independently tricyclic. In some cases, the heterocycle is tricyclic. In some cases, the carbocycle is tricyclic. [00188] In some embodiments, for a compound or salt of Formula (II), B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from , each of which is optionally substituted with one or more substituents.
  • the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from , each of which is optionally substituted with one or more substituents.
  • the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from, , each of which is optionally substituted with one or more substituents.
  • the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from oxo, -NH 2 , -CN, halogen, C 1 -C 3 alkyl.
  • the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH 2 , halogen, C 1 -C 3 alkyl.
  • B is selected from
  • each R 4 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, hydroxyl, halogen. Ins some cases, each R 4 is independently selected from C 1-6 alkyl, oxo, and halogen.
  • n is selected from 1 and 2. In some cases, n is 0.
  • Y is O.
  • R 1 is selected from optionally substituted 5- to 12-membered heterocycle.
  • R 1 is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR 20 ) 2 , -OR 20 , SR 20 , - S(O) 2 (R 20 ), -S(O) 2 N(R 20 ) 2 , -NR 20 S(O) 2 R 20 , -C(O)N(R 20 ) 2 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 ) 2 , -N(R 20 )C(O)OR 20 ,-N(R 20 ) 2 , -C(O)R 20 , C(O)OR 20 , -OC(O)R 20 , -OC(O)N(R 20 ) 2 , -NO 2
  • R 1 is selected from C 3 - C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from -S(O) 2 (R 20 ), -S(O) 2 N(R 20 ) 2 , -NR 20 S(O) 2 R 20 , -N(R 20 )C(O)OR 20 , and -OC(O)N(R 20 ) 2 .
  • R 1 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R 20 ) 2 , - NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, and C 1-6 haloalkyl.
  • R 20 of R 1 is selected from hydrogen and C 1-3 alkyl.
  • the 5- to 12-membered heterocycle of R 1 is an unsaturated heterocycle.
  • the 5- to 12-membered heterocycle of R 1 is a saturated heterocycle.
  • 5- to 12-membered heterocycle of R 1 is a bridged heterocycle.
  • R 1 is selected from , which is optionally substituted.
  • the optional one or more substituents are independently selected from halogen, -CN, -NHCN, C 1-6 cyanoalkyl, and C 1-6 alkyl.
  • the optional one or more substituents are independently selected from -CN, -NHCN, C 1-6 cyanoalkyl, and C 1-6 alkyl.
  • the optional one or more substituents are independently selected from -CN, -NHCN, C 1-6 cyanoalkyl, and C 1-6 alkyl.
  • the optional one or more substituents are independently selected from -NHCN, and C 1-6 alkyl.
  • the optional substituents of L are selected from C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkyl, C 3 -C 6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle or 3- to 8-membered heterocycle wherein the C 3 -C 6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen and C 1-6 haloalkyl.
  • each L is independently selected from a substituted C 1 -C 4 alkylene, wherein two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle.
  • each L is independently selected from a substituted C 1 -C 4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle.
  • each L is independently selected from a substituted C 3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle.
  • each L is independently selected from .
  • R 2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R 6 .
  • the heterocycle is a saturated heterocycle.
  • the heterocycle has at least one nitrogen atom and at least one sulfur atom.
  • the heterocycle has at least one nitrogen atom.
  • the heterocycle has at least one sulfur atom.
  • R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from and , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • R 2 is selected from -L- saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R 6 , and contains one nitrogen atom and one sulfur atom.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more substituents selected from C 1 -C 3 alkyl and oxo.
  • each R 6 is independently selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, -CN, and C 1 -C 3 aminoalkyl.
  • each R 6 is independently selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, -N(R 5 ) 2 , and oxo.
  • each R 6 is independently selected from -OH, Cl- C3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 alkoxy, and -N(R 5 ) 2 .
  • each R 6 is independently selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and -N(R 5 ) 2 .
  • R 6 is selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, -CN, and C 1 -C 3 aminoalkyl.
  • R 6 is selected from halogen and C 1 -C 3 alkyl.
  • R 6 is halogen.
  • R 6 is C 1 -C 3 alkyl.
  • R 6 is selected from halogen and C 1 -C 3 alkyl. In some cases, R 6 is selected from methyl and fluorine.
  • R 2 is selected from [00225] In some embodiments, for a compound or salt of Formula (II), Y-R 2 is selected from [00226] In some embodiments, for a compound or salt of Formula (II), Y-R 2 is selected from [00227] In some embodiments, for a compound or salt of Formula (II), Y-R 2 is . [00228] In some embodiments, for a compound or salt of Formula (II), Y-R 2 is selected from , and .
  • L is selected from C 1 - C4 alkylene.
  • L is selected from unsubstituted C 1 -C 4 alkylene.
  • R 2 is -L-heterocycle, optionally substituted with one or more R 6 , wherein the heterocycle portion is a bicyclic heterocycle.
  • the bicyclic heterocycle contains at least 1 nitrogen atom. In some cases, the bicyclic heterocycle contains at most 1 nitrogen atom.
  • R 2 is selected from L- bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R 6 .
  • R 2 is selected from L- pyrrolizine, wherein the pyrrolizine is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • R 6 of R 2 is independently selected at each occurrence from halogen, hydroxy, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, cyano, and C 1 -C 3 aminoalkyl. In some cases, R 6 of R 2 is independently selected at each occurrence from C 1 -C 3 alkyl and halogen. In some cases, Y-R 2 is [00236] In some embodiments, for a compound or salt of Formula (II), M is selected from NR 3 . In some cases, M is selected from NH and NMe.
  • M is selected from NMe and NCH 2 CH3. In some cases, M is NMe. In some cases, M is selected from C 1-6 cyanoalkyl. In some cases, M is selected from C 2 cyanoalkyl. In some cases, M is selected from NH. In some cases, R 3 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxyalkyl, and C 1-6 haloalkyl.
  • R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkyl-N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxyalkyl, and C 1-6 haloalkyl. In some cases, R 3 is selected from C 1-6 alkyl, C 1-6 alkyl-N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxyalkyl, and C 1-6 haloalkyl.
  • R 3 is selected from C 2-6 alkyl, C 1-6 alkyl- N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxyalkyl, and C 1- 6 haloalkyl. In some cases, R 3 is selected from C 1-6 alkyl-N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1 - 6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxyalkyl, and C 1-6 haloalkyl.
  • R 3 is selected from C 1-6 cyanoalkyl, C 1-6 alkoxyalkyl, and C 1-6 haloalkyl. In some cases, R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkyl-N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, and C 1-6 haloalkyl. In some cases, R 3 is selected from C 1-6 alkoxyalkyl, C 1-6 cyanoalkyl, and C 1-6 alkyl. In some cases, R 3 is . In some cases, R 3 is selected from C 2-6 alkyl.
  • M is NR 3
  • B is selected from , each of which is optionally substituted; n is 0; Y is O; R 2 is selected from L-heterocycle, wherein the heterocycle is optionally substituted with one or more R 6 ; R 1 is
  • heterocycle of L-heterocycle is bicyclic. In some cases, the heterocycle of L-heterocycle is monocyclic.
  • L is selected from an C 1 -C4 alkylene. In some cases, L is selected from an unsubstituted C 1 -C4 alkylene. In some cases, L is independently selected from a substituted C 1 -C 4 alkylene, wherein two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle.
  • Y-R 2 is selected from , , which is substituted with one or more substituents. In some cases, , which is substituted with one or more substituents.
  • B is selected from , which is substituted with one or more substituents.
  • B is substituted with at least one halogen.
  • B is substituted with at least one chlorine.
  • B is substituted with at least one fluorine.
  • haloalkyl and C 1-6 haloalkyl.
  • B is selected from , which is substituted with one or more substituents selected from fluorine.
  • B is substituted with one or more substituents selected from chlorine.
  • B is selected from .
  • R 3 is selected from hydrogen and C 1-6 alkyl.
  • R 3 is selected from C 1-6 alkyl.
  • R 3 is methyl.
  • each R 6 is selected from halogen, oxo, and C 1-6 alkyl.
  • R 1 is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR 20 ) 2 , -OR 20 , -SR 20 , - S(O) 2 (R 20 ), -C(O)N(R 20 ) 2 , -C(O)NR 20 -OR 20 , -S(O) 2 N(R 20 ) 2 , -NR 20 S(O) 2 R 20 , -N(R 20 )C(O)R 20 , - N(R 20 )C(O)N(R 20 ) 2 , -N(R 20 )C(O)OR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , -
  • R 2 is selected from -L- NR 21 S(O) 2 (R 21 ) and -L-S(O) 2 N(R 21 ) 2 .
  • R 2 is selected from -L- N(R 21 )C(O)(OR 21 ), and -L-OC(O)N(R 21 ) 2 .
  • each R 21 is independently selected from hydrogen; C 1-6 alkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO 2 , -NH 2 , -N(C 1-6 alkyl) 2 , C 1-10 alkyl, -C 1-10 haloalkyl, -O- C 1-10 alkyl, and oxo.
  • each R 21 is independently selected from hydrogen; C 1-6 alkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle.
  • each R 21 is independently selected from hydrogen and C 1-6 alkyl.
  • R 2 is selected from L- bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R 6 .
  • R 2 is selected from L- pyrrolizine, wherein the pyrrolizine is optionally substituted with one or more R 6 .
  • B is an optionally substituted 5- to 15-membered heterocycle or optionally substituted C 3 -C 15 carbocycle.
  • B is an optionally substituted 5- to 15-membered heterocycle. In some cases, B is an optionally substituted 8- to 15-membered heterocycle. In some cases, B is an optionally substituted C 3 -C 15 carbocycle. In some cases, B is an optionally substituted C 8 -C 15 carbocycle. [00246] In some embodiments, for a compound or salt of Formula (III), B is an optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted C8-C15 fused carbocycle.
  • the optionally substituted 8- to 15-membered heterocycle contains at least one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least two heteroatoms.
  • the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15- membered fused heterocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle are each bicyclic or tricyclic. [00249] In some embodiments, for a compound or salt of Formula (III), B the heterocycle or carbocycle are each independently bicyclic.
  • the heterocycle is bicyclic. In some cases, the carbocycle is bicyclic. [00250] In some embodiments, for a compound or salt of Formula (III), B the heterocycle or carbocycle are each independently tricyclic. In some cases, the heterocycle is tricyclic. In some cases, the carbocycle is tricyclic. [00251] In some embodiments, for a compound or salt of Formula (III), B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from , each of which is optionally substituted with one or more substituents.
  • the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C 8 -C 15 fused carbocycle is selected from , [00253] In some embodiments, for a compound or salt of Formula (III), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C 8 -C 15 fused carbocycle is selected from, , each of which is optionally substituted with one or more substituents.
  • the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from oxo, -NH 2 , -CN, halogen, C 1 -C 3 alkyl.
  • the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH 2 , halogen, C 1 -C 3 alkyl.
  • B is selected from , , , , , ,
  • the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH 2 , halogen, C 1 -C 3 alkyl.
  • B is selected from .
  • each R 4 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, hydroxyl, halogen. Ins some cases, each R 4 is independently selected from C 1-6 alkyl, oxo, and halogen.
  • n is selected from 1 and 2. In some cases, n is 0. [00260] In some embodiments, for a compound or salt of Formula (III), Y is O. [00261] In some embodiments, for a compound or salt of Formula (III), R 1 is selected from optionally substituted 5- to 12-membered heterocycle.
  • R 1 is selected from C 3 - C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR 20 ) 2 , -OR 20 , SR 20 , - S(O) 2 (R 20 ), -S(O) 2 N(R 20 ) 2 , -NR 20 S(O) 2 R 20 , C(O)N(R 20 ) 2 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 ) 2 , - N(R 20 )C(O)OR 20 ,-N(R 20 ) 2 , -C(O)R 20 , C(O)OR 20 , -OC(O)R 20 , -OC(O)N(R 20 ) 2 , -NO 2 ,
  • R 1 is selected from C 3 - C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR 20 ) 2 , -OR 20 , SR 20 , - S(O) 2 (R 20 ), -S(O) 2 N(R 20 ) 2 , -NR 20 S(O) 2 R 20 , C(O)N(R 20 ) 2 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 ) 2 , - N(R 20 )C(O)OR 20 ,-N(R 20 ) 2 , -C(O)R 20 , C(O)OR 20 , -OC(O)R 20 , -OC(O)N(R 20 ) 2 , -NO 2 ,
  • R 1 is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from -S(O) 2 (R 20 ), -S(O) 2 N(R 20 ) 2 , -NR 20 S(O) 2 R 20 , -N(R 20 )C(O)OR 20 , and -OC(O)N(R 20 ) 2 .
  • R 1 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R 20 ) 2 , - NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, and C 1-6 haloalkyl.
  • R 20 of R 1 is selected from hydrogen and C 1-3 alkyl.
  • the 5- to 12-membered heterocycle of R 1 is an unsaturated heterocycle.
  • the 5- to 12-membered heterocycle of R 1 is a saturated heterocycle.
  • 5- to 12-membered heterocycle of R 1 is a bridged heterocycle.
  • R 1 is selected from ,
  • R 1 is selected from [00274]
  • R 1 is selected from an optionally substituted saturated 6- to 7-membered heterocycle.
  • R 1 is selected from an optionally substituted saturated 6-membered heterocycle. In some cases, R 1 is selected from , which is optionally substituted. In some cases, the optional one or more substituents are independently selected from halogen, -CN, -NHCN, C 1-6 cyanoalkyl, and C 1-6 alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C 1-6 cyanoalkyl, and C 1-6 alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C 1-6 cyanoalkyl, and C 1-6 alkyl.
  • the optional one or more substituents are independently selected from -NHCN, and C 1-6 alkyl.
  • R 1 is selected from , which is substituted with one or more substituents selected from -NHCN, and C 1-6 alkyl.
  • R 1 is selected from , and .
  • L is selected from C 1 - C4 alkylene.
  • the optional substituents of L are selected from C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkyl, C 3 -C 6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle or 3- to 8-membered heterocycle wherein the C 3 -C 6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen and C 1-6 haloalkyl.
  • each L is independently selected from a substituted C 1 -C 4 alkylene, wherein two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle.
  • each L is independently selected from a substituted C 1 -C 4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle.
  • each L is independently selected from a substituted C 3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle.
  • each L is independently selected from .
  • R 2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R 6 .
  • the heterocycle is a saturated heterocycle.
  • the heterocycle has at least one nitrogen atom and at least one sulfur atom.
  • the heterocycle has at least one nitrogen atom.
  • the heterocycle has at least one sulfur atom.
  • R 2 is selected from wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from [00285] In some embodiments, for a compound or salt of Formula (III), R 2 is selected from -L- saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R 6 , and contains one nitrogen atom and one sulfur atom. In some cases, Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 . In some cases, Y-R 2 is selected from , , , wherein the heterocycle portion is optionally substituted with one or more substituents selected from C 1 -C 3 alkyl and oxo.
  • each R 6 is independently selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, -CN, and C 1 -C 3 aminoalkyl.
  • each R 6 is independently selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, -N(R 5 ) 2 , and oxo.
  • each R 6 is independently selected from -OH, Cl- C3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 alkoxy, and -N(R 5 ) 2 .
  • each R 6 is independently selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and -N(R 5 ) 2 .
  • R 6 is selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, -CN, and C 1 -C 3 aminoalkyl.
  • R 6 is selected from halogen and C 1 -C 3 alkyl.
  • R 6 is halogen.
  • R 6 is C 1 -C 3 alkyl.
  • R 6 is selected from halogen and C 1 -C 3 alkyl. In some cases, R 6 is selected from methyl and fluorine.
  • R 2 is selected from [00291] In some embodiments, for a compound or salt of Formula (III), Y-R 2 is selected from [00292] In some embodiments, for a compound or salt of Formula (III), Y-R 2 is selected from [00293] In some embodiments, for a compound or salt of Formula (III), Y-R 2 is . [00294] In some embodiments, for a compound or salt of Formula (III), L is selected from unsubstituted C 1 -C4 alkylene.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • R 6 of R 2 is independently selected at each occurrence from halogen, hydroxy, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, cyano, and C 1 -C 3 aminoalkyl.
  • R 6 of R 2 is independently selected at each occurrence from C 1 -C 3 alkyl and halogen.
  • Y-R 2 is selected from .
  • the carbocycle of R 1 is selected from C 3 -C 12 carbocycle, C3-C10 carbocycle, C3-C9 carbocycle, C 3 -C 8 carbocycle, or C 3 -C 6 carbocycle.
  • the carbocycle of R 1 is selected from C 3 -C 12 carbocycle, C 4 -C 12 carbocycle, C 5 -C 12 carbocycle, C 6 -C 12 carbocycle, C 7 -C 12 carbocycle, C8-C12 carbocycle, or C9-C12 carbocycle.
  • the heterocycle of R 1 is a 5- to 12-membered heterocycle, 6- to 12-membered heterocycle, 7- to 12-membered heterocycle, or 8- to 12-membered heterocycle.
  • the heterocycle of R 1 is a 5- to 11-membered heterocycle, 5- to 10-membered heterocycle, 5- to 9-membered heterocycle, or 5- to 8-membered heterocycle.
  • the heterocycle of R 1 is a 6- to 11-membered heterocycle, 6- to 10- membered heterocycle, 6- to 9-membered heterocycle, or 6- to 8-membered heterocycle.
  • the heterocycle of R 1 is a 7- to 11-membered heterocycle, 7- to 10-membered heterocycle, 7- to 9-membered heterocycle, or 7- to 8-membered heterocycle.
  • the heterocycle of R 1 is a 5- to 6-membered heterocycle or 5- to 9-membered heterocycle. In some cases, the heterocycle of R 1 is an 8- to 9-membered heterocycle. In some cases, the heterocycle of R 1 is saturated. The heterocycle may be optionally substituted as described elsewhere herein. [00301] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the heterocycle of R 1 is a 5- to 12-membered monocyclic heterocycle, 6- to 12-membered monocyclic heterocycle, 7- to 12-membered monocyclic heterocycle, or 8- to 12-membered monocyclic heterocycle.
  • the heterocycle of R 1 is a 5- to 11-membered monocyclic heterocycle, 5- to 10-membered monocyclic heterocycle, 5- to 9-membered monocyclic heterocycle, or 5- to 8-membered monocyclic heterocycle.
  • the heterocycle of R 1 is a 6- to 11-membered monocyclic heterocycle, 6- to 10-membered monocyclic heterocycle, 6- to 9-membered monocyclic heterocycle, or 6- to 8-membered monocyclic heterocycle.
  • the heterocycle of R 1 is a monocyclic 7- to 11-membered heterocycle, 7- to 10-membered monocyclic heterocycle, 7- to 9-membered monocyclic heterocycle, or 7- to 8-membered monocyclic heterocycle.
  • the heterocycle of R 1 is a 5- to 6-membered monocyclic heterocycle or 5- to 9-membered monocyclic heterocycle.
  • the heterocycle of R 1 is an 8- to 9-membered monocyclic heterocycle.
  • the heterocycle of R 1 is saturated.
  • the monocyclic heterocycle may be optionally substituted as described elsewhere herein.
  • the heterocycle of R 1 is a 5- to 12-membered bridged heterocycle, 6- to 12-membered bridged heterocycle, 7- to 12-membered bridged heterocycle, or 8- to 12-membered bridged heterocycle.
  • the heterocycle of R 1 is a 5- to 11-membered bridged heterocycle, 5- to 10-membered bridged heterocycle, 5- to 9-membered bridged heterocycle, or 5- to 8- membered bridged heterocycle.
  • the heterocycle of R 1 is a 6- to 11-membered bridged heterocycle, 6- to 10-membered bridged heterocycle, 6- to 9-membered bridged heterocycle, or 6- to 8-membered bridged heterocycle.
  • the heterocycle of R 1 is a bridged 7- to 11-membered heterocycle, 7- to 10-membered bridged heterocycle, 7- to 9- membered bridged heterocycle, or 7- to 8-membered bridged heterocycle.
  • the heterocycle of R 1 is a 5- to 6-membered bridged heterocycle or 5- to 9-membered bridged heterocycle.
  • the heterocycle of R 1 is an 8- to 9-membered bridged heterocycle.
  • the heterocycle of R 1 is saturated.
  • the bridged heterocycle may be optionally substituted as described elsewhere herein.
  • R 1 is a 5- to 9-membered heterocycle, the 5- to 9- membered heterocycle contains at most 1 nitrogen atom.
  • R 1 is selected from optionally substituted 5- to 9- membered heterocycle, each of which is optionally substituted.
  • the heterocycle of R 1 contains at most 1 nitrogen atom. In some embodiments, the heterocycle of R 1 contains at most 1 heteroatom atom.
  • the heterocycle of R 1 contains at most 2 heteroatom atoms.
  • the heteroatom is selected from nitrogen, oxygen, and sulfur.
  • the heterocycle is a monocyclic heterocycle or a bridged heterocycle.
  • the heterocycle is a monocyclic heterocycle.
  • the heterocycle is a bridged heterocycle.
  • the heterocycle is selected from .
  • the heterocycle is selected from , , , , and .
  • the bridged heterocycle is selected from , , .
  • the heterocycle may be optionally substituted as described elsewhere herein.
  • the spiroheterocycle of R 1 contains at most 1 nitrogen atom. In some embodiments, the spiroheterocycle of R 1 contains at most 2 heteroatom atoms. In some embodiments, the spiroheterocycle of R 1 contains at most 3 heteroatom atoms. In some embodiments, the spiroheterocycle of R 1 contains at most 1 heteroatom atom. In some cases, the spiroheterocycle of R 1 contains at least 2 heteroatom atoms. In some cases, the spiroheterocycle of R 1 contains at least 3 heteroatom atoms.
  • the spiroheterocycle of R 1 contains at least 4 heteroatom atoms. In some cases, the spiroheterocycle of R 1 contains at least 2 nitrogen atoms. In some embodiments, the spiroheterocycle of R 1 contains at most 1 heteroatom atom. In some cases, the spiroheterocycle of R 1 contains at most 1 sulfur atom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some embodiments, the spiroheterocycle of R 1 is
  • the spiroheterocycle of R 1 is selected from The spiroheterocycle may be optionally substituted as described elsewhere herein.
  • R 1 is selected from optionally substituted 7- to 8-membered spiroheterocycle. In some cases, R 1 is selected from optionally substituted 7-membered spiroheterocycle. In some cases, R 1 is selected from optionally substituted 8-membered spiroheterocycle.
  • the fused heterocycle of R 1 is a 6- to 12-membered fused heterocycle, 6- to 12-membered fused heterocycle, 7- to 12-membered fused heterocycle, or 8- to 12-membered fused heterocycle.
  • the fused heterocycle of R 1 is a 6- to 11-membered fused heterocycle, 6- to 10-membered fused heterocycle, 6- to 9-membered fused heterocycle, or 6- to 8-membered fused heterocycle.
  • the fused heterocycle of R 1 is a 7- to 11- membered fused heterocycle, 7- to 10-membered fused heterocycle, 7- to 9-membered fused heterocycle, or 7- to 8-membered fused heterocycle.
  • the fused heterocycle of R 1 is an 8- to 11-membered fused heterocycle.
  • the fused heterocycle of R 1 is a 6- membered fused heterocycle. The fused heterocycle may be optionally substituted as described elsewhere herein.
  • the fused heterocycle of R 1 is selected from a 6-, 9-, 10-, 11-, and 12-membered fused heterocycle. In some cases, the fused heterocycle of R 1 is selected from a 9- to 12-membered fused heterocycle. In some cases, the fused heterocycle of R 1 is selected from a 10- to 12- membered fused heterocycle.
  • the fused heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -N(R 20 ) 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy,C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • the fused heterocycle of R 1 contains at most 1 nitrogen atom. In some embodiments, the fused heterocycle of R 1 contains at most 1 heteroatom atom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some cases, the fused heterocycle i . fused heterocycle may be optionally substituted as described elsewhere herein.
  • R 1 is selected from C6-C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which is optionally substituted.
  • R 1 is selected from C 6 -C 7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 8- to 12-membered fused heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -N(R 20 ) 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • R 1 is selected from C 6 -C 7 carbocycle and 5- to 10-membered heterocycle, each of which is optionally substituted. In some cases, the heterocycle contains at most 1 nitrogen atom. In some cases, R 1 is selected from C 6 -C 7 carbocycle, each of which is optionally substituted.
  • the one or more optional substituents of R 1 are independently selected from halogen, -OR 20 , -N(R 20 ) 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, - N(R 20 )C(O)N(R 20 ) 2 , and C 1-6 alkyl.
  • one or more optional substituents of R 1 are independently selected from halogen, -OR 20 , - N(R 20 ) 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • the one or more optional substituents of R 1 are independently selected from -OR 20 , - N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, and C 1-6 alkyl.
  • the one or more optional substituents of R1 are independently selected from -OR 20 , -N(R 20 ) 2 , C 1-6 aminoalkyl, and C 1-6 hydroxyalkyl. In some cases, the one or more optional substituents of R1 are independently selected from -OR 20 , -N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkyl, and C 1-6 hydroxyalkyl. In some cases, the one or more optional substituents of R 1 are independently selected from -OR 20 , -N(R 20 ) 2 , and C 1-6 alkyl.
  • R 1 is selected from C 3 -C 12 carbocycle and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R 1 is further selected from 7-, 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle wherein the C 3 -C 12 carbocycle, 5- to 12-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, are each optionally substituted with one or more substituents
  • R 1 is selected from C 3 -C 12 carbocycle and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R 1 is further selected from 7-, 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle wherein the C 3 -C 12 carbocycle, 5- to 12-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, are each optionally substituted with one or more substituents independently selected from halogen, -B(OR 20 ) 2 , - OR 20 , -SR 20 , -N(R 20 ) S(
  • substituted with one or more substituents independently selected from halogen, -N(R 20 ) 2 , C 1-6 alkyl, -OR 20 , -N(R 20 )C(O)N(R 20 ) 2 , -B(OR 20 ) 2 , C 1-6 cyanoalkyl, -N(R 20 )C(O)N(R 20 ) 2 , O, C 1-6 hydroxyalkyl, halogen, -N(R 20 )C(O)R 20 , -N(R 20 ) S(O) 2 (R 20 ), and C 1-6 aminoalkyl.
  • substituents independently selected from halogen, -N(R 20 ) 2 , C 1-6 alkyl, -OR 20 , -N(R 20 )C(O)N(R 20 ) 2 , -B(OR 20 ) 2 , C 1-6 cyanoalkyl, -N(R 20 )C(O)N(R
  • R 1 is selected from 5- to 10-membered heterocycle, wherein the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from - OR 20 , -N(R 20 ) 2 , C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, -N(R 20 )C(O)N(R 20 ) 2 , - N(R 20 )C(O)R 20 , and -B(OR 20 ) 2 .
  • R 1 is selected from , , , , , each of which is optionally substituted with one or more substituents independently selected from -OR 20 , -N(R 20 ) 2 , C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, - N(R 20 )C(O)N(R 20 ) 2 , -N(R 20 )C(O)R 20 , and -B(OR 20 ) 2 .
  • R 1 is selected from 5- to 10-membered heterocycle, wherein the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from - N(R 20 ) 2 , -OR 20 , and C 1-6 alkyl. In some cases, the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from -OR 20 , and C 1-6 alkyl.
  • R 1 is selected from , each of which is optionally substituted with one or more substituents independently selected from -OR 20 , and C 1-6 alkyl. In some cases, R 1 is selected [00324] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula , each of which are optionally substituted. [00325] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from , each of which is optionally substituted with one or more substituents independently selected from -OH, -CN, oxo, C 1-6 cyanoalkyl.
  • R 1 is selected from , , , each of which are optionally substituted.
  • R 1 is selected from each of which are optionally substituted.
  • R 1 is which is optionally substituted.
  • R 1 is which is optionally substituted for a compound or salt of Formula (I), Formula (II), or Formula (III).
  • Y-R 2 is selected from wherein the heterocycle portion is optionally substituted.
  • R 1 is selected from an optionally substituted 5- to 12-membered unsaturated heterocycle, wherein the heterocycle has as most one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at least one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at most one nitrogen atom.
  • R 1 is selected from 6- to 7-membered heterocycle.
  • R 1 is selected from 7- membered heterocycle. In some cases, R 1 is selected from 6-membered heterocycle. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur. In some cases, the optionally one or more additional heteroatoms are selected from sulfur. In some cases, the optionally one or more additional heteroatoms are selected from oxygen. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms. In some cases, the 6- to 7- membered heterocycle is a non-aromatic 6- to 7-membered heterocycle.
  • the 6- to 7-membered heterocycle of R 1 is bound to Formula (I) via the only 1 nitrogen atom. In some cases, the 6- to 7-membered heterocycle of R 1 is bound to Formula (II) via the only 1 nitrogen atom. In some cases, the 6- to 7-membered heterocycle of R 1 is bound to Formula (III) via the only 1 nitrogen atom. In some cases, R 1 is selected from , each of which is substituted. In some cases, R 1 is selected from , , , , , each of which is substituted.
  • the one or more optional substituents of R 1 are each independently selected from halogen, -OH, -CN, C 1-6 cyanoalkyl, C 1-6 alkyl, and C 2-6 alkynyl.
  • the one or more optional substituents of R 1 are each independently selected from halogen, -OH, and -CN. In some cases, the one or more optional substituents of R 1 are each independently selected from fluorine, -OH, -CN, C 1-6 cyanoalkyl, C 1-6 alkyl, oxo, and C 2-6 alkynyl. In some cases, the one or more optional substituents of R 1 are each independently selected from fluorine, -OH, -CN, C 1-6 ,
  • R 1 is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. In some cases, R 1 is selected from an optionally substituted unsaturated 6-membered heterocycle. In some cases, R 1 is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, the heterocycle has 1 or 2 double bonds. In some cases, the heterocycle has only 1 double bond. In some cases, the heterocycle has only 2 double bonds.
  • R 1 is selected from wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl. In some cases, R 1 is wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • R 1 is selected from wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl. In some cases, R 1 is . , . , , wherein each is substituted with one or more substituents independently selected from halogen.
  • R 1 is selected from an unsaturated 6- to 7-membered heterocycle, wherein the unsaturated 6- to 7-membered heterocycle is substituted with one or more substituents selected from halogen.
  • the unsaturated 6- to 7-membered heterocycle is substituted with at least one halogen.
  • the unsaturated 6- to 7-membered heterocycle is substituted with at only one halogen.
  • the unsaturated 7-membered heterocycle is substituted with one fluorine.
  • R 1 is selected from an unsaturated 6-membered heterocycle, substituted with at least one halogen.
  • R 1 is selected from an unsaturated 7-membered heterocycle
  • R 1 is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle.
  • R 1 is selected from an optionally substituted unsaturated 7-membered heterocycle.
  • R 1 is selected from , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH 2 , - NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • R 1 is selected from [00340]
  • R 1 is selected from an optionally substituted 6-membered heterocycle.
  • the 6- membered heterocycle contains only 1 nitrogen atom.
  • the 6-membered heterocycle of R 1 is bound to Formula (I) via the only 1 nitrogen atom.
  • the 6-membered heterocycle of R 1 is bound to Formula (II) via the only 1 nitrogen atom.
  • the 6- membered heterocycle of R 1 is bound to Formula (III) via the only 1 nitrogen atom.
  • R 1 is selected from , any of which is optionally substituted.
  • the 6-membered heterocycle is a partially unsaturated 6-membered heterocycle or a saturated 6- membered heterocycle. In some cases, the 6-membered heterocycle is partially unsaturated. In some cases, the 6-membered heterocycle is a saturated 6-membered heterocycle. In some cases, the 6-membered heterocycle is a monocyclic 6-membered heterocycle. In some cases, the 6- membered heterocycle is not a bridged heterocycle. In some cases, R 1 is selected from
  • R 1 is selected from an optionally substituted 6-membered unsaturated heterocycle and 6- membered saturated heterocycle.
  • R 1 is selected from , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • R 1 is selected from , wherein each is optionally substituted with one or more substituents independently selected from halogen, and C 1-6 haloalkyl.
  • R 1 is selected from [00344] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from [00345] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from , wherein each is optionally substituted two substituents independently selected from halogen, -OH, -NH 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • R 1 is selected from , wherein each is optionally substituted with two substituents independently selected from halogen, and C 1-6 haloalkyl. In some cases, R 1 is . [00347] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III),R 1 is selected from an optionally substituted 6- to 10-membered heterocycle. In some cases, the 6- to 10-membered heterocycle contains at least 1 nitrogen atom.
  • each R 20 is independently selected from hydrogen; and C 1-6 alkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO 2 , -NH 2 , -N(C 1-6 alkyl) 2 , C 1-10 alkyl, -C 1-10 haloalkyl, -O-C 1-10 alkyl, oxo, C 3-12 carbocycle, and 3- to 12-membered heterocycle.
  • R 1 is selected from
  • R 1 is selected from an optionally substituted 10-membered heterocycle.
  • the 10-membered heterocycle is a bicyclic heterocycle.
  • the 10-membered heterocycle is a spiro heterocycle.
  • the 10-membered heterocycle is a fused heterocycle.
  • the 10-membered heterocycle is a saturated heterocycle.
  • the 10-membered heterocycle is a non-aromatic heterocycle.
  • the 10- membered heterocycle contains at least 1 nitrogen atom.
  • the 10-membered heterocycle contains at least 2 nitrogen atoms.
  • the 10-membered heterocycle contains at least 3 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 1 sulfur atom.
  • R 1 is selected from an optionally substituted unsaturated 9- to 11-membered heterocycle. In some cases, R 1 is selected from an optionally substituted unsaturated 10- membered heterocycle. In some cases, R 1 is selected from an optionally substituted unsaturated 10-membered fused heterocycle. In some cases, , which is optionally substituted.
  • each R 20 is independently selected from hydrogen; and C 1-6 alkyl, and C 3-12 carbocycle, and each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO 2 , -NH 2 , C 1-10 alkyl, -C 1-10 haloalkyl, -O-C 1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle.
  • R 1 is selected from a 7- to 11-membered spiro heterocycle.
  • R 1 is selected from a 10-membered spiro heterocycle. In some cases, the spiro heterocycle has at least 3 nitrogen atoms. In some cases, the spiro heterocycle has at least 1 sulfur atom. In some cases, R 1 is selected from , each of which is optionally substituted.
  • R 1 is selected some cases, R 1 is .
  • M is selected from O, and NR 3 . In some cases, M is selected from O. In some cases, M is selected from NR 3 . In some cases, R 3 is selected from C 1-6 alkyl.
  • R 3 is selected from C 1 -2 alkyl. In some cases, R 3 is selected from methyl.
  • R 1 is selected from an optionally substituted 8- to 10-membered fused heterocycle.
  • the 8- to 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 8- to 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 8- to 10- membered fused heterocycle is an unsaturated heterocycle. In some cases, the 8- to 10- membered heterocycle is a non-aromatic heterocycle.
  • R 1 is selected from an optionally substituted 9-membered fused heterocycle. In some cases, R 1 is selected from an optionally substituted 10-membered fused heterocycle. In some cases, the 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 9-membered heterocycle is a non-aromatic heterocycle. In some cases, the 10-membered heterocycle is a non-aromatic heterocycle. In some cases, the fused heterocycle has one saturated ring and one aromatic ring. In some cases, the fused heterocycle has one saturated ring and one unsaturated ring. In some cases, the fused heterocycle has two saturated rings.
  • the 10-membered heterocycle contains at least 1 nitrogen atom. In some cases, the 10-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 3 nitrogen atoms. In some cases, the 9- membered heterocycle contains at least 1 nitrogen atom. In some cases, the 9-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 9-membered heterocycle contains at least 3 nitrogen atoms. In some cases, R 1 is selected from , each of which is optionally substituted with one or more substituents. In some cases, R 1 is , which is optionally substituted with one or more substituents.
  • R 1 is , which is optionally substituted with one or more substituents.
  • the optional one or more substituents are independently selected from -C(O)R 20 , -C(O)N(R 20 ) 2 , and -C(O)NR 20 OR 20 .
  • the further one or more optional substituents are selected from halogen, -CN, C2 alkenyl, and C 1-6 alkyl. In some cases, the further one or more optional substituents are selected from halogen, and C 1-6 alkyl. In some cases, the further one or more optional substituents are selected from halogen.
  • each R 20 is independently selected from hydrogen; and C 1-6 alkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R 20 is independently selected from hydrogen; and C 1-6 alkyl, and 3- to 12- membered heterocycle. In some cases, each R 20 is independently selected from hydrogen; and C 1-6 alkyl, and 3- to 12-membered saturated heterocycle.
  • each R 20 is independently selected from 5- to 6-membered saturated heterocycle.
  • the heterocycle of R 20 has at least one nitrogen atom.
  • the heterocycle of R 20 has at least one sulfur atom.
  • the heterocycle of R 20 has at least one oxygen atom.
  • the heterocycle of R 20 contains only 1 heteroatom.
  • the heterocycle of R 20 has at least two heteroatoms.
  • the heterocycle of R 20 contains only 2 heteroatoms.
  • the optional one or more substituents of R 1 are independently optional one or more substituents of R 1 are independently selected from halogen, , , some cases, the optional one or more substituents of R 1 are or more substituents of R 1 are independently selected from ,
  • R 1 is independently selected from halogen, and C 1-6 alkyl-N(R 20 ) 2 .
  • the optional one or more substituents of R 1 are independently selected from halogen, . , ydrogen, C 1-6 alkyl, and C 3-6 carbocycle.
  • R 1 is selected , some cases, R 1 is selected
  • R 1 is selected from , which is optionally substituted with one more substituents independently selected from halogen and C 1-6 alkyl. In some cases, R 1 is selected from . [00352] In some embodiments, for a compound or salt of Formula (I), Formula (II), or selected from a 5- to 12- membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R 1* ; and R B is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkynyl, and -CN. In some cases, R B is selected from hydrogen, and halogen. In some cases, R B is chloride. In some cases, R B is hydrogen.
  • heteroatoms In some cases, 2, 3, or 4 heteroatoms. In some cases, has at least 1, 2, 3, or 4 nitrogen atoms. In some cases, has at least 1 oxygen atom. In some cases, is a monocyclic heterocycle. In some cases, is a bicyclic heterocycle. In some cases, is selected from an optionally substituted 5-membered heterocycle. In some cases, is selected from an optionally substituted with one or more R 1* . In some cases, , is optionally substituted with one or more R 1* .
  • each R 1* is independently selected from halogen, C 1-6 alkyl-N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, and C 1-6 alkyl. In some cases, each R 1* is independently selected from halogen, and C 1-6 alkyl. In some cases, , , , [00353] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), when R 1 is substituted with -C(O)R 20 , R 20 is selected from a 5- to 12- membered heterocycle, which is optionally substituted.
  • R 1 is substituted with - C(O)R 20 .
  • R 20 is selected from a 5- to 12-membered unsubstituted heterocycle.
  • R 20 is selected from a 5- to 6-membered heterocycle, which is optionally substituted.
  • the heterocycle has at least one nitrogen atom.
  • the heterocycle has at least one sulfur atom.
  • the heterocycle has at least one oxygen atom.
  • the heterocycle has two heteroatoms.
  • the heterocycle of R 20 is selected , each of which is optionally substituted.
  • R 1 is an optionally substituted 12- to 15-membered heterocycle.
  • R 1 is an optionally substituted 12-membered heterocycle. In some cases, R 1 is an optionally substituted 13-membered heterocycle. In some cases, R 1 is an optionally substituted 14- membered heterocycle. In some cases, R 1 is an optionally substituted 15-membered heterocycle. In some cases, the heterocycle of R 1 is tricyclic. In some cases, the heterocycle of R 1 contains a fused heterocycle. In some cases, the heterocycle of R 1 contains a spiro-heterocycle. In some cases, the heterocycle of R 1 contains a fused and spiro-heterocycle. In some cases, the heterocycle of R 1 is an unsaturated heterocycle.
  • the heterocycle of R 1 is a non- aromatic heterocycle. In some cases, the heterocycle of R 1 has at least one double bond. In some cases, the heterocycle of R 1 has at least two double bonds. In some cases, the heterocycle of R 1 has at least 2 heteroatoms. In some cases, the heterocycle of R 1 has at least 3 heteroatoms. In some cases, the heterocycle of R 1 has at least 4 heteroatoms. In some cases, the heterocycle of R 1 has at least 5 heteroatoms. In some cases, the heterocycle of R 1 has at least 6 heteroatoms. In some cases, the heterocycle of R 1 has at least 7 heteroatoms. In some cases, the heteroatoms are selected from oxygen, nitrogen, and sulfur.
  • the heterocycle of R 1 has at least 3, 4, or 5 nitrogen atoms, and at least 1 sulfur atom. In some cases, the heterocycle of R 1 has at least 3, 4, or 5 nitrogen atoms, and at least 1 oxygen atom. In some cases, the heterocycle of R 1 has at least 3, 4, or 5 nitrogen atoms. In some cases, the heterocycle of R 1 has at least 3, 4, or 5 nitrogen atoms and no other heteroatoms. In some cases, the heteroatoms are selected from nitrogen and sulfur. In some cases, the heteroatoms are selected from nitrogen and oxygen. In , each of which is optionally substituted with one or more substituents.
  • R 1 is , , , , , , , , each of which is optionally substituted with one or more substituents.
  • R 1 is an optionally substituted 12- to 15-membered heterocycle.
  • R 1 wherein Ring W is an optionally substituted heterocycle and Ring P is an optionally substituted carbocycle or optionally substituted heterocycle, wherein Ring P forms a spirocycle with Ring W.
  • Ring W is an optionally substituted fused heterocycle.
  • Ring P and Ring W combine to form a heterocycle having at least 12 atoms and most 15 atoms.
  • Ring P and Ring W have in total at least 12 atoms and most 15 atoms.
  • Ring W is an optionally substituted 10-membered fused heterocycle.
  • Ring P is an optionally substituted carbocycle or optionally substituted heterocycle.
  • Ring P is an optionally substituted carbocycle.
  • Ring P is an optionally substituted heterocycle.
  • Ring P forms an optionally substituted C 3 -C 6 carbocycle or optionally substituted 4-to 6-membered heterocycle.
  • Ring P forms an optionally substituted C3 carbocycle.
  • Ring P forms an optionally substituted C4 carbocycle.
  • Ring P forms an optionally substituted C5 carbocycle.
  • Ring P forms an optionally substituted 4-membered heterocycle.
  • Ring P forms an optionally substituted 5-membered heterocycle. In some cases, Ring P forms an optionally substituted 5-membered heterocycle. In some cases, Ring P has at least 1, 2, or 3 heteroatoms. In some cases, the heteroatoms are selected from oxygen, nitrogen, and sulfur. In some cases, Ring P has 1 sulfur atom. In some cases, Ring P has 1 nitrogen atom. In some cases, Ring P has 1 oxygen atom.
  • the one or more optional substituents of Ring W are independently selected from -C(O)R 20 .
  • Ring P is substituted.
  • Ring W is substituted.
  • R 1 is selected from , , , , .
  • R 2 is selected from optionally substituted -L-heterocycle.
  • the heterocycle is a bicyclic heterocycle.
  • the heterocycle is a monocyclic heterocycle.
  • the heterocycle has only 1 nitrogen atom.
  • the heterocycle has only 1 nitrogen atom and no other heteroatoms.
  • Y-R 2 is selected from substituted.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted.
  • R 2 is selected from -L-N(R 21 ) 2 .
  • each R 21 is selected from hydrogen and C 1-6 alkyl.
  • each R 21 is selected from C 1-6 alkyl.
  • L is independently selected from a substituted C 1 -C 4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle, wherein the C 3 -C 6 carbocycle is optionally substituted with one or more substituents selected from halogen.
  • R 2 is .
  • each R 21 is independently selected from hydrogen. In some cases, each R 21 is independently selected from hydrogen and C 1-6 alkyl. In some cases, each R 21 is independently selected from C 1-6 alkyl.
  • each R 21 is independently selected from hydrogen; and C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO 2 , -NH 2 , -N(C 1-6 alkyl) 2 , C 1-10 alkyl, -C 1-10 haloalkyl, -O-C 1-10 alkyl, oxo.
  • R 1 is selected from an optionally substituted 8- to 10-membered fused heterocycle.
  • the 8- to 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 8- to 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 8- to 10-membered heterocycle is a non-aromatic heterocycle. In some cases, R 1 is selected from an optionally substituted 9-membered fused heterocycle. In some cases, R 1 is selected from an optionally substituted 10-membered fused heterocycle. In some cases, the 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 10-membered heterocycle is a non-aromatic heterocycle.
  • the fused heterocycle has one saturated ring and one aromatic ring. In some cases, the fused heterocycle has one saturated ring and one unsaturated ring. In some cases, the fused heterocycle has two saturated rings. In some cases, the 10-membered heterocycle contains at least 1 nitrogen atom. In some cases, the 9-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 9-membered heterocycle contains at least 3 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 10- membered heterocycle contains at least 3 nitrogen atoms. In some cases, R 1 is selected from , which is optionally substituted with one or more substituents.
  • the optional one or more substituents are independently selected from -C(O)R 20 , -C(O)N(R 20 ) 2 , and - C(O)NR 20 OR 20 . In some cases, the optional one or more substituents are independently selected from -C(O)R 20 . In some cases, the optional one or more substituents are independently selected from -C(O)N(R 20 ) 2 . In some cases, the optional one or more substituents are independently selected from -C(O)NR 20 OR 20 . In some cases, each R 20 is independently selected from hydrogen; and C 1-6 alkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle.
  • each R 20 is independently selected from hydrogen; and C 1-6 alkyl, and 3- to 12-membered heterocycle. In some cases, each R 20 is independently selected from hydrogen; and C 1-6 alkyl, and 3- to 12- membered saturated heterocycle. In some cases, the optional one or more substituents of R 1 are
  • R 1 is selected from an optionally substituted saturated 6- to 7-membered heterocycle. In some cases, R 1 is selected from an optionally substituted saturated 6-membered heterocycle. In some cases, R 1 is selected from , which is optionally substituted. In some cases, the optional one or more substituents are independently selected from halogen, -CN, -NHCN, C 1-6 cyanoalkyl, and C 1-6 alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C 1-6 cyanoalkyl, and C 1-6 alkyl.
  • the optional one or more substituents are independently selected from -CN, -NHCN, C 1-6 cyanoalkyl, and C 1-6 alkyl. In some cases, the optional one or more substituents are independently selected from -NHCN, and C 1-6 alkyl. In some cases, R 1 is selected from , which is substituted with one or more substituents selected from -NHCN, and C 1-6 alkyl. In some cases, R 1 is selected from , and .
  • R 1 is selected from a substituted saturated 6-membered heterocycle, wherein the saturated 6-membered heterocycle is substituted with at least one -NHCN, and optionally one or more C 1-6 alkyl;
  • Ring A is selected from an optionally substituted heterocycle;
  • Y is O;
  • R 2 is selected from -L-heterocycle, wherein the heterocycle portion is optionally substituted with one or more substitu
  • R 1 is selected from , and [00364]
  • B is an optionally substituted 8- to 10-membered fused carbocycle.
  • B is a substituted 8- to 10-membered fused carbocycle.
  • B is an unsubstituted 8- to 10- membered fused carbocycle.
  • B is an optionally substituted 9-membered fused carbocycle.
  • B is a substituted 9-membered fused carbocycle.
  • B is , which is optionally substituted with one or more substituents.
  • B is , which is substituted with one or more substituents.
  • B is substituted with at least one halogen.
  • B is substituted with at least one chlorine.
  • B is substituted with at least one fluorine.
  • B is selected selected from halogen and C 1-6 haloalkyl. In some cases, , which is substituted with one or more substituents selected from halogen. In some cases, B is selected from , , which is substituted with one or more substituents selected from fluorine. In some cases, B is substituted with one or more substituents selected from chlorine. In some cases, B is selected from . some cases, B is a substituted 10-membered fused carbocycle.
  • B is In some cases, for the 10-membered fused carbocycle of B, is substituted with at least one , . some cases, B is an unsubstituted 9- to 10-membered fused carbocycle. In some cases, B is selected , each of which is unsubstituted.
  • the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least oxygen atom. In some cases, the heterocycle has at least one nitrogen atom and at least one oxygen atom. In some cases, heterocycle has at least two heteroatoms. In some cases, the heterocycle has at least three heteroatoms. In some cases, the heterocycle has at least four heteroatoms. In some cases, the heterocycle of the one or more optional substituents of R 1 is selected from , optionally substituted with one or more R 1* . In some cases, the heterocycle of the one or more optional substituents of R 1 is selected from , which is optionally substituted with one or more R 1* .
  • each R 1* is independently selected from halogen, C 1-6 alkyl-N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, and C 1-6 alkyl. In some cases, each R 1* is independently selected from halogen, C 1-6 haloalkyl, and C 1-6 alkyl. In some cases, each R 1* is independently selected from halogen, and C 1-6 alkyl. In some cases, each R 1* is independently selected from halogen. In some cases, each R 1* is independently selected from C 1-6 alkyl. In some cases, each R 1* is independently selected from -OR 20 .
  • each R 1* is independently selected from halogen, C 1-6 alkyl-N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, and C 1-6 alkyl. In some cases, each R 1* is independently selected from halogen, C 1-6 haloalkyl, and C 1-6 alkyl. In some cases, each R 1* is independently selected from halogen, and C 1-6 alkyl. In some cases, each R 1* is independently selected from halogen. In some cases, each R 1* is independently selected from C 1-6 alkyl.
  • R 1 is selected from 5- to 15-membered heterocycle (preferably 8- to 10-membered heterocycle or preferably 10-membered heterocycle), each of which are optionally substituted with one or more substituents independently selected from halogen, oxo, -C(O)N(R 20 ) 2 , - C(O)NR 20 OR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -SO 2 R 20 , -NHCN, C 1-6 cyanoalkyl, C 1-6 alkyl, C 1-6 alkyl-N(R 20 ) 2 , C 2-6 alkynyl, and 5- to 12-membered heterocycle (preferably 5- to 9- membered heterocycle), wherein the 5- to 12-membered heterocycle are each optionally substituted independently with one or more R 1* ; each
  • the 8- to 10-membered heterocycle is bicyclic. In some cases, the 10-membered heterocycle is substituted. In some cases, R 1 is selected , , , , and , each of which is optionally substituted. In some cases, R 1 is selected , which is optionally substituted. In some cases, R 1 is selected ,
  • R 1 is selected from 5- to 15-membered heterocycle (preferably 8- to 10-membered heterocycle or preferably 10-membered heterocycle), each of which are optionally substituted with one or more substituents independently selected from halogen, -C(O)N(R 20 ) 2 , - C(O)NR 20 OR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -NHCN, C 1-6 cyanoalkyl, C 1-6 alkyl, C 2-6 alkynyl, and 5- to 12-membered heterocycle (preferably 5- to 6-membered heterocycle), wherein the 5- to 12-membered heterocycle are each optionally substituted independently with one or more R 1* ; each R 1* is independently selected from halogen, C 1-6 haloalkyl, and C 1-6 alkyl.
  • the 8- to 10-membered heterocycle is bicyclic. In some cases, the 10-membered heterocycle is substituted. In some cases, R 1 is selected , , , each of which is optionally substituted. In some cases, R 1 is selected , which is optionally substituted. In
  • M is selected from O, and NMe. In some cases, M is O. In some cases, M is NMe.
  • R 2 is selected from -L-N(R 21 ) 2 and -L-heterocycle, optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , , some cases, B is selected from an optionally substituted carbocycle. In some cases, B is selected from substituted. In some cases, B is selected from , . , . [00371]
  • R 1 is selected from a compound in the Examples section.
  • Y is selected from a compound in the Examples section.
  • L is selected from a compound in the Examples section.
  • R 2 is selected from a compound in the Examples section.
  • B is selected from a compound in the Examples section..
  • M is selected from a compound in the Examples section.
  • the optional substituents of the heterocycle for R 1 is selected from a compound in the Examples section. [00372]
  • R 2 is -L-N(R 21 ) 2 .
  • R 2 is -L-OR 21 .
  • R 2 is heterocycle.
  • the heterocycle, the aryl portion of - L-NR 21 C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L- cycloalkyl are each optionally substituted with one or more R 6 , and wherein the aryl portion of the -L- aryl and the heteroaryl portion of the -L-heteroaryl are each optionally substituted with one or more R 7 .
  • R 1 is selected from an optionally substituted 7- to 10-membered spiro heterocycle and optionally substituted 7- to 10- membered fused heterocycle.
  • the heterocycle of R 1 has at least one nitrogen atom.
  • the at least one nitrogen at of the heterocycle of R 1 is bound to Formula (II*).
  • R 1 is selected from an optionally substituted 10-membered spiro heterocycle and optionally substituted 10-membered fused heterocycle.
  • B is optionally substituted with one or more substituents independently selected from halogen. In some cases, . some cases, . some cases, B is unsubstituted. In some cases, B is substituted.
  • R 1 is selected from an optionally substituted 7- to 10-membered spiro heterocycle and optionally substituted 7- to 10- membered fused heterocycle. In some cases, R 1 is selected from an optionally substituted 10- membered spiro heterocycle and optionally substituted 10-membered fused heterocycle. In some cases, R 1 is selected from an optionally substituted 10-membered spiro heterocycle.
  • R 1 is selected from an optionally substituted 10-membered fused heterocycle.
  • the heterocycle of R 1 has at least 3 heteroatoms.
  • M is selected from O. In some cases, M is NMe.
  • the heterocycle of R 2 is a saturated heterocycle.
  • L of R 2 is selected from C 1 -C4 alkylene . is optionally substituted.
  • B is optionally substituted with one or more substituents independently selected from halogen.
  • B is unsubstituted.
  • B is substituted.
  • the heterocycle or carbocycle of R 1 is not substituted by C 1-6 cyanoalkyl. In some embodiments, for a compound or salt of Formula (I), the heterocycle or carbocycle of R 1 is not substituted by C 1-6 cyanoalkyl. In some embodiments, for a compound or salt of Formula (II), the heterocycle or carbocycle of R 1 is not substituted by C 1-6 cyanoalkyl. In some embodiments, for a compound or salt of Formula (III), the heterocycle or carbocycle of R 1 is not substituted by C 1-6 cyanoalkyl.
  • each R 20 is independently selected from hydrogen; and C 1-6 alkyl.
  • each R 20 is independently selected from hydrogen; and C 1-6 alkyl.
  • each R 20 is independently selected from hydrogen; and C 1-6 alkyl.
  • R 1 is not a piperazine. In some cases, R 1 is not a substituted piperazine.
  • a compound of Formula (I) wherein the compound is not a Michael acceptor.
  • the compound or salt does not include an electrophilic substituent.
  • the compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III) does not contain an electrophile moiety.
  • a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III) does not contain a covalent modifier.
  • the one or more optional substituents of R 1 are not electrophiles.
  • the compounds of Formula (I), (II), (II*), (III), or subformulas used in the methods include trifluoroacetic acid salts of the above compounds.
  • the compound or salt of Formula (II) is administered to a subject at about 5 mg to about 500 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 150 mg.
  • the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 125 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 25 mg to about 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the compound or salt of Formula (II) of is administered to a subject at about 5 mg to about 75 mg.
  • the compound or salt of Formula (II) is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg , about 30 mg, about 45 mg, or about 60 mg.
  • the compound or salt of Formula (II) is administered to a subject at about 15 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 30 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 45 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 60 mg. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.
  • a compound or salt of Formula (II) is administered once daily. In some embodiments, the compound or salt of Formula (II) is administered twice daily. In some embodiments, the compound or salt of Formula (II) is administered 3 times daily. In some embodiments, the compound or salt of Formula (II) is administered once weekly. In some embodiments, the compound or salt of Formula (II) is administered every other day. In some embodiments, the compound or salt of Formula (II) is administered every 3 days. [00388] In some embodiments, the compound or salt of Formula (II) is administered to a subject at 10 mg to 150 mg.
  • the compound or salt of Formula (II) or a salt thereof is administered to a subject at 10 mg to 125 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 10 mg to 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 25 mg to 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 50 mg to 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 5 mg to 75 mg.
  • the compound or salt of Formula (II) is administered to a subject at 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg.
  • the compound or salt of Formula (II) is administered to a subject at 15 mg, 30 mg, 45 mg, or 60 mg.
  • the compound or salt of Formula (II) is administered to a subject at 15 mg.
  • the compound or salt of Formula (II) is administered to a subject at 30 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 45 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 60 mg. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old. [00389] In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 150 mg, daily.
  • the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 125 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 25 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 50 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 5 mg to about 75 mg, daily.
  • the compound or salt of Formula (II) is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg, daily.
  • the compound or salt of Formula (II) is administered to a subject at about 15 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 30 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 45 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 60 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered once daily. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult.
  • the subject is greater than or equal to 18 years old.
  • the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 150 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 125 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 100 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 25 mg to about 100 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 50 mg to about 100 mg, twice daily.
  • the compound or salt of Formula (II) is administered to a subject at about 5 mg to about 75 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg, twice daily.
  • the compound or salt of Formula (II) is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 30 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 45 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 60 mg, twice daily. In some embodiments, the subject is between 12 years old to 18 years old.
  • the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old. [00391] In some embodiments, a compound of Formula (II) is administered as a capsule during the period of time.
  • a tablet or capsule formulation of a compound of Formula (II) comprises about 10 mg to about 100 mg (e.g., about 10 mg to about 95 mg, about 10 mg to about 90 mg, about 10 mg to about 85 mg, about 10 mg to about 80 mg, about 10 mg to about 75 mg, about 10 mg to about 70 mg, about 10 mg to about 65 mg, about 10 mg to about 60 mg, about 10 mg to about 55 mg, about 10 mg to about 50 mg, about 10 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 15 mg to about 100 mg, about 15 mg to about 95 mg, about 15 mg to about 90 mg, about 15 mg to about 85 mg, about 15 mg to about 80 mg, about 15 mg to about 75 mg, about 15 mg to about 70 mg, about 15 mg to about 65 mg, about 15 mg to about 60 mg, about 15 mg to about 55 mg, about 15 mg to about
  • a compound of Formula (II) is orally administered once a day (QD) on a daily basis during a period of time. In one embodiment, a compound of Formula (II) is orally administered twice a day (BID) on a daily basis during a period of time.
  • a compound of Formula (II) is orally administered in the amount of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 500 mg, about 40 mg to about 480 mg, about 40 mg to about 460 mg,
  • the combination therapy comprises oral administration of a compound of Formula (II) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg (e.g., about 10 mg to about 380 mg, about 10 mg to about 360 mg, about 10 mg to about 340 mg, about 10 mg to about 320 mg, about 10 mg to about 300 mg, about 10 mg to about 280 mg, about 10 mg to about 260 mg, about 10 mg to about 240 mg, about 10 mg to about 220 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 140 mg, about 10 mg to about 120 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 40 mg, about 10 mg to about 20 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 400 mg, about 20 mg
  • the inhibitor is an immunomodulator inhibitor. In some cases, the inhibitor is an PD-1 inhibitor. In some cases, the inhibitor is an PD-L1 inhibitor. In some cases, the inhibitor is an CTLA-4 inhibitor. In some cases, the compound of Formula (II) is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is selected compound 53, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 61 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 63 or a pharmaceutically acceptable salt of any one thereof.
  • the compound of Formula (II) is compound 64 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 69 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 96, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is orally administered once daily. In one embodiment, the compound of Formula (II) is orally administered twice daily. [00394] In some embodiments, a compound of Formula (II), or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered as a tablet or capsule.
  • a tablet or capsule formulation of a compound of Formula (II) comprises about 10 mg to about 100 mg (e.g., about 10 mg to about 95 mg, about 10 mg to about 90 mg, about 10 mg to about 85 mg, about 10 mg to about 80 mg, about 10 mg to about 75 mg, about 10 mg to about 70 mg, about 10 mg to about 65 mg, about 10 mg to about 60 mg, about 10 mg to about 55 mg, about 10 mg to about 50 mg, about 10 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 15 mg to about 100 mg, about 15 mg to about 95 mg, about 15 mg to about 90 mg, about 15 mg to about 85 mg, about 15 mg to about 80 mg, about 15 mg to about 75 mg, about 15 mg to about 70 mg, about 15 mg to about 65 mg, about 15 mg to about 60 mg, about 15 mg to about 55 mg, about 15 mg to about
  • a compound is selected form
  • a compound of Formula (II) is orally administered once a day (QD) on a daily basis during a period of time.
  • a compound of Formula (II) is orally administered twice a day (BID) on a daily basis during a period of time.
  • a compound of Formula (II) is orally administered in the amount of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 500 mg, about 40 mg to about 480 mg, about 40 mg to about 460 mg,
  • the compound of Formula (II) is selected compound 53, or a pharmaceutically acceptable salt of any one thereof.
  • the compound of Formula (II) is compound 61 or a pharmaceutically acceptable salt of any one thereof.
  • the compound of Formula (II) is compound 63 or a pharmaceutically acceptable salt of any one thereof.
  • the compound of Formula (II) is compound 64 or a pharmaceutically acceptable salt of any one thereof.
  • the compound of Formula (II) is compound 69 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 96, or a pharmaceutically acceptable salt of any one thereof. [00395] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein.
  • the compounds of the present invention that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt.
  • compounds that are inherently charged can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
  • an appropriate counterion e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
  • Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.
  • a “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • the compounds disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • the compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.
  • the methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs).
  • the compounds described herein may be in the form of pharmaceutically acceptable salts.
  • active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester.
  • prodrug is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure.
  • One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal.
  • esters or carbonates are preferred prodrugs of the present disclosure.
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein are included within the scope of the claims.
  • some of the herein-described compounds may be a prodrug for another derivative or active compound.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.
  • the design of a prodrug increases the lipophilicity of the pharmaceutical agent.
  • the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed.
  • the compounds may be synthesized using conventional techniques.
  • these compounds are conveniently synthesized from readily available starting materials.
  • Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).
  • compositions comprising a therapeutically effective amount of a compound of Formulas (I), (II), (II*), (III), an immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor, or a pharmaceutically acceptable salt of any one thereof (also referred to herein as “a pharmaceutical agent”).
  • a pharmaceutical agent also referred to herein as “a pharmaceutical agent”.
  • Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • compositions and methods of the present disclosure may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the composition or the pharmaceutical agent When administered to an animal, such as a human, the composition or the pharmaceutical agent, is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient.
  • Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as an eye drop.
  • a pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • carbohydrates such as glucose, sucrose or dextrans
  • antioxidants such as ascorbic acid or glutathione
  • chelating agents low molecular weight proteins or other stabilizers or excipients.
  • the choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a self emulsifying drug delivery system or a self microemulsifying drug delivery system.
  • the pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically
  • a pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion.
  • the excipients described herein are examples and are in no way limiting.
  • An effective amount or therapeutically effective amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein.
  • Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and/or in the urine, and/or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.
  • the dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art.
  • Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts.
  • suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration.
  • Optimal doses of an agent may generally be determined using experimental models and/or clinical trials.
  • the optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre- clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art.
  • the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy.
  • two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone.
  • An amount of a pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg/kg and 100 mg/kg, e.g., between about 0.1 to 1 mg/kg, between about 1 to 10 mg/kg, between about 10-50 mg/kg, between about 50-100 mg/kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg/kg and 1000 mg/kg, between about 100-500 mg/kg, or between about 500-1000 mg/kg body weight.
  • the optimal dose, per day or per course of treatment may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen.
  • compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art.
  • the composition may be in the form of a solid, e.g., tablet, capsule, semi-solid, e.g., gel, liquid, or gas, e.g., aerosol.
  • the pharmaceutical composition is administered as a bolus infusion.
  • Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5 th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub.
  • compositions described herein may be formulated as a lyophilizate.
  • a composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and/or diluting the pharmaceutical agent(s) of the composition upon administration.
  • the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art.
  • a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries.
  • Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art.
  • a pharmaceutical composition e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may be in the form of a liquid.
  • a liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile.
  • a liquid pharmaceutical composition for treatment of an ophthalmological condition or disease, may be applied to the eye in the form of eye drops.
  • a liquid pharmaceutical composition may be delivered orally.
  • at least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents.
  • the pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and/or an enteric coating.
  • a pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and/or with an enteric coating.
  • a pharmaceutical composition comprising any one of the pharmaceutical agents described herein may be formulated for sustained or slow release, also called timed release or controlled release.
  • sustained or slow release also called timed release or controlled release.
  • Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site.
  • Sustained-release formulations may contain the compound dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane.
  • compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration.
  • the compositions can be administered using a syringe, bandage, transdermal patch, insert, or syringe- like applicator, as a powder/talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste.
  • the active compositions can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms.
  • Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.
  • Pharmaceutical compositions comprising a pharmaceutical agent can be formulated as emulsions for topical application. An emulsion contains one liquid distributed in the body of a second liquid.
  • the emulsion may be an oil-in-water emulsion or a water-in-oil emulsion.
  • Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients.
  • the oil phase may contain other oily pharmaceutically approved excipients.
  • Suitable surfactants include, but are not limited to, anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants.
  • Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Liquid sprays may be delivered from pressurized packs, for example, via a specially shaped closure.
  • Oil-in-water emulsions can also be used in the compositions, patches, bandages and articles. These systems are semisolid emulsions, micro-emulsions, or foam emulsion systems.
  • the pharmaceutical agent described herein can be formulated as in inhalant. Inhaled methods can deliver medication directly to the airway.
  • the pharmaceutical agent can be formulated as aerosols, microspheres, liposomes, or nanoparticles.
  • the pharmaceutical agent can be formulated with solvents, gases, nitrates, or any combinations thereof.
  • Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles.
  • Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.
  • Aerosolized formulations described herein are optionally delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having with a mass medium average diameter predominantly between 1 to 5 ⁇ .
  • the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the pharmaceutical agent.
  • the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.
  • Aerosolization devices suitable for administration of aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-5 ⁇ . Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 ⁇ range.
  • a jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate.
  • An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets.
  • a variety of suitable devices are available, including, for example, AeroNeb ⁇ ⁇ and AeroDose ⁇ ⁇ ⁇ vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream ⁇ nebulizers (Medic-Aid Ltd., West Wales, England), Pari LC ⁇ and Pari LC Star ⁇ jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and Aerosonic ⁇ ⁇ (DeVilbiss Medizinische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische
  • the pharmaceutical agent(s) can be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape.
  • these semisolid compositions can contain dissolved and/or suspended bactericidal agents, preservatives and/or a buffer system.
  • a petrolatum component that may be included may be any paraffin ranging in viscosity from mineral oil that incorporates isobutylene, colloidal silica, or stearate salts to paraffin waxes.
  • Absorption bases can be used with an oleaginous system.
  • Additives may include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.
  • Controlled or sustained release transdermal or topical formulations can be achieved by the addition of time-release additives, such as polymeric structures, matrices, that are available in the art.
  • the compositions may be administered through use of hot-melt extrusion articles, such as bioadhesive hot-melt extruded film.
  • the formulation can comprise a cross- linked polycarboxylic acid polymer formulation.
  • a cross-linking agent may be present in an amount that provides adequate adhesion to allow the system to remain attached to target epithelial or endothelial cell surfaces for a sufficient time to allow the desired release of the compound.
  • An insert, transdermal patch, bandage or article can comprise a mixture or coating of polymers that provide release of the pharmaceutical agents at a constant rate over a prolonged period of time.
  • the article, transdermal patch or insert comprises water- soluble pore forming agents, such as polyethylene glycol (PEG) that can be mixed with water insoluble polymers to increase the durability of the insert and to prolong the release of the active ingredients.
  • PEG polyethylene glycol
  • Transdermal devices may also comprise a water insoluble polymer.
  • Rate controlling polymers may be useful for administration to sites where pH change can be used to effect release. These rate controlling polymers can be applied using a continuous coating film during the process of spraying and drying with the active compound.
  • the coating formulation is used to coat pellets comprising the active ingredients that are compressed to form a solid, biodegradable insert.
  • a polymer formulation can also be utilized to provide controlled or sustained release. Bioadhesive polymers described in the art may be used. By way of example, a sustained-release gel and the compound may be incorporated in a polymeric matrix, such as a hydrophobic polymer matrix.
  • Examples of a polymeric matrix include a microparticle.
  • the microparticles can be microspheres, and the core may be of a different material than the polymeric shell.
  • the polymer may be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel.
  • the polymer can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent.
  • the matrices can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art.
  • kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating disease, and optionally an appliance or device for delivery of the composition.
  • KITS AND PRODUCTS Immunomodulator inhibitor combination Kit [00437] Some embodiments relate to kits and products that include the compound or salt of Formula (II) and/or an immunomodulator inhibitor.
  • the kit or product can include a package or container with a compound of Formula (II) or pharmaceutically acceptable salt.
  • kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound or salt of Formula (II) in combination with an immunomodulator inhibitor that is separately provided.
  • the kits can be used in the methods of treating cancer as described herein.
  • kits or products can include both a compound or salt of Formula (II) and an immunomodulator inhibitor.
  • kits can include one or more containers or packages, which include one or both combination drugs together in a single container and/or package, or in separate packages/containers. In some instances, the two drugs are separately wrapped, but included in a single package, container or box.
  • kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound or salt of Formula (II) in combination with an immunomodulator inhibitor.
  • the kits can be used in the methods of treating cancer as described herein.
  • kits and products that include the compound or salt of Formula (II) and/or at least one PD-1 inhibitor.
  • the kit or product can include a package or container with a compound or salt of Formula (II).
  • kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound or salt of Formula (II) in combination with an PD-1 inhibitor that is separately provided.
  • the kits can be used in the methods of treating cancer as described herein.
  • kits or products can include both a compound of Formula (II) and at least one PD-1 inhibitor.
  • kits can include one or more containers or packages, which include one or both combination drugs together in a single container and/or package, or in separate packages/containers. In some instances, the two drugs are separately wrapped, but included in a single package, container or box.
  • kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound or salt of Formula (II) in combination with an PD-1 inhibitor.
  • the kits can be used in the methods of treating cancer as described herein.
  • kits and products that include the compound of Formula (II) and/or at least one PD-L1 inhibitor.
  • the kit or product can include a package or container with a compound or salt of Formula (II).
  • kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound or salt of Formula (II) in combination with an PD-L1 inhibitor that is separately provided.
  • the kits can be used in the methods of treating cancer as described herein.
  • kits or products can include both a compound of Formula (II) and at least one PD-L1 inhibitor.
  • kits can include one or more containers or packages, which include one or both combination drugs together in a single container and/or package, or in separate packages/containers. In some instances, the two drugs are separately wrapped, but included in a single package, container or box.
  • kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound or salt of Formula (II) in combination with an PD-L1 inhibitor.
  • the kits can be used in the methods of treating cancer as described herein.
  • kits and products that include the compound of Formula (II) and/or at least one CTLA-4 inhibitor.
  • the kit or product can include a package or container with a compound of Formula (II).
  • kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound of Formula (II) in combination with an CTLA-4 inhibitor that is separately provided.
  • the kits can be used in the methods of treating cancer as described herein.
  • kits or products can include both a compound or salt of Formula (II) and at least one CTLA-4 inhibitor.
  • kits can include one or more containers or packages, which include one or both combination drugs together in a single container and/or package, or in separate packages/containers. In some instances, the two drugs are separately wrapped, but included in a single package, container or box.
  • kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound of Formula (II) in combination with an CTLA-4 inhibitor. The kits can be used in the methods of treating cancer as described herein.
  • the compound or salt of Formula (II) is selected from compounds 53, 61, 63, 64, 69, and 96.
  • DOSINGS [00453]
  • the dosage regimen for the compounds herein e.g, an immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor; or a compound or salt of Formula (II), or a pharmaceutical composition of any one thereof
  • the dosing frequency for the therapeutic agent may vary, for example, from once per day to six times per day. That is, the dosing frequency may be QD, i.e., once per day, BID, i.e., twice per day; TID, i.e., three times per day; QID, i.e., four times per day; five times per day, or six times per day.
  • dosing frequency may be BIW, i.e., twice weekly, TIW, i.e., three times a week, or QIW, i.e. four times a week.
  • the treatment cycle may have a period of time where no therapeutic agent is administered.
  • val administration refers to administration of the therapeutic agent (e.g, an immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor; or a compound or salt of Formula (II)) followed by void days or void weeks.
  • the treatment cycle may be 3 weeks long which includes 2 weeks of dosing of the therapeutic agent(s) followed by 1 week where no therapeutic agent is administered. In some embodiments, the treatment cycle is 4 weeks long which includes 3 weeks of dosing followed by 1 week where no therapeutic agent is administered.
  • the daily oral dosage of each active ingredient e.g, immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor; or a compound or salt of Formula (II)
  • each active ingredient e.g, immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor; or a compound or salt of Formula (II)
  • the daily oral dosage of each active ingredient when used for the indicated effects, will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about l00 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day.
  • an active ingredient e.g, an immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor; or a compound or salt of Formula (II)
  • an active ingredient may be administered at a dose of between about 10 mg/day and about 200 mg/day.
  • an active ingredient e.g, an immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor; or a compound or salt of Formula (II)
  • an active ingredient may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day.
  • the dose may be any value or subrange within the recited ranges.
  • treatment cycle means a pre-determined period of time for administering the therapeutic agent (e.g, an immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor; or a compound or salt of Formula (II)).
  • the patient is examined at the end of each treatment cycle to evaluate the effect of the therapy.
  • each of the treatment cycle has about 3 or more days.
  • each of the treatment cycle has from about 3 days to about 60 days.
  • each of the treatment cycle has from about 5 days to about 50 days.
  • each of the treatment cycle has from about 7 days to about 28 days.
  • each of the treatment cycle has 28 days.
  • the treatment cycle has about 29 days. In some cases, the treatment cycle has about 30 days. In some cases, the treatment cycle has about 31 days. In some cases, the treatment cycle has about a month-long treatment cycle. In some cases, the treatment cycle is any length of time from 3 weeks to 8 weeks. In some cases, the treatment cycle is any length of time from 3 weeks to 6 weeks. In some cases, the treatment cycle is 3 weeks. In some cases, the treatment cycle is one month. In some cases, the treatment cycle is 4 weeks. In some cases, the treatment cycle is 5 weeks. In some cases, the treatment cycle is 6 weeks. In some cases, the treatment cycle is 7 weeks. In some cases, the treatment cycle is 8 weeks.
  • the duration of the treatment cycle may include any value or subrange within the recited ranges, including endpoints.
  • drugs are administered at the maximum tolerated dose (“MTD”), which is the highest dose of drug that does not cause unacceptable side effects.
  • MTD maximum tolerated dose
  • Immunomodulator inhibitor Dosing [00457] In some embodiments, the immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof is administered prior to administration of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof. [00458] In some embodiments, the immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, is administered after administration of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
  • the immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof is administered at about the same time as administration of the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof.
  • separate administration of each inhibitor/compound, at different times and by different routes, may be advantageous.
  • the components in the combination i.e. compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, and the immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof need not be necessarily administered at essentially the same time or in any order.
  • a pharmaceutical composition comprises an immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprises a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions may be used in the methods simultaneously, separately, or sequentially.
  • a pharmaceutical composition comprises an immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, and/or a compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, for use in the methods for simultaneous, separate or sequential use.
  • the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at their respective MTDs.
  • the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is dosed at its MTD and the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed in an amount less than its MTD.
  • the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is dosed at an amount less than its MTD and the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD.
  • the compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at less than their respective MTDs.
  • the administration can be so timed that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.
  • the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered QD. In some cases, the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are administered BID. In some cases, the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID. [00463] In some embodiments, a single dose of compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each administered once daily.
  • the therapeutically effective amount of the immunomodulator inhibitor of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day. In some embodiments, the therapeutically effective amount of the immunomodulator inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the immunomodulator inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day.
  • the therapeutically effective amount of the immunomodulator inhibitor of the combination may be any value or subrange within the recited ranges.
  • the therapeutically effective amount of the immunomodulator inhibitor of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day. In some embodiments, the therapeutically effective amount of the immunomodulator inhibitor of the combination will range between about 0.1 to about 50 mg/kg of body weight. In some embodiments the therapeutically effective amount of the immunomodulator inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the immunomodulator inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day.
  • the therapeutically effective amount of the immunomodulator inhibitor of the combination may be any value or subrange within the recited ranges.
  • the immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, and the compound of Formula (II), or a pharmaceutically acceptable salt thereof can be formulated into separate or individual dosage forms which can be co- administered one after the other.
  • the route of administration is the same (e.g. oral) two active compounds can be formulated into a single form for co-administration, both methods of co-administration, however, being part of the same therapeutic treatment or regimen.
  • the combination therapy comprises oral administration of a compound of Formula (II) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg and oral administration of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time).
  • the combination therapy comprises oral administration of a compound of Formula (II) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg and oral administration of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time).
  • the combination therapy comprises oral administration of a compound of Formula (II) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg and oral administration of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time).
  • the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 5 mg to about 600 mg.
  • the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 10 mg to about 150 mg.
  • the immunomodulator inhibitor is administered to a subject at about 10 mg to about 125 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 440 mg to about 520 mg. In some embodiments, the immunomodulator inhibitor is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the immunomodulator inhibitor is administered to a subject at about 25 mg to about 100 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof of is administered to a subject at about 5 mg to about 75 mg.
  • the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 170 mg, about 190 mg, about 210 mg, about 240 mg, about 300 mg, about 350 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 540 mg, about 580 mg, or about 650 mg.
  • the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg , about 30 mg, about 45 mg, or about 60 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 30 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 45 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 60 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 240 mg.
  • the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 480 mg. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old. [00468] In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered once daily. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered twice daily. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered 3 times daily. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered once weekly.
  • the immunomodulator inhibitor, or pharmaceutically salt thereof is administered every other day. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered every 3 days. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered once a week. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered every two weeks. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered every 4 weeks. [00469] In some embodiments, the immunomodulator inhibitor is administered intravenously in the amount of about 800 mg every 2 weeks (Q2W) or about 10 mg/kg every 2 weeks (Q2W). In one embodiment, the immunomodulator inhibitor, is administered intravenously over 60 minutes.
  • the immunomodulator inhibitor is administered at a dose of 1200 mg intravenously once every 3 weeks (Q3W) or at a dose of 840 mg intravenously two weeks apart. In some cases, the immunomodulator inhibitor, is administered intravenously over 60 minutes. [00471] In some embodiments, the immunomodulator inhibitor, is administered at a dose of 10 mg/kg intravenously once every 2 weeks (Q2W). In one embodiment, the immunomodulator inhibitor, is administered intravenously over 60 minutes.
  • a pharmaceutical composition comprises a PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprises a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions may be used in the methods simultaneously, separately, or sequentially.
  • a pharmaceutical composition comprises a PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, and/or a compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, for use in the methods which may be for simultaneous, separate or sequential use.
  • the PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered prior to administration of the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered after administration of the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at about the same time as administration of the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • separate administration of each inhibitor, at different times and by different routes, may be advantageous.
  • the components in the combination i.e.
  • the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and the PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof may need not to be administered at essentially the same time or in any order.
  • the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at their respective MTDs.
  • the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is dosed at its MTD and the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed in an amount less than its MTD. In some cases, the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at an amount less than its MTD and the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD.
  • the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at less than their respective MTDs. In some cases, the administration can be so timed that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.
  • the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered QD. In some cases, the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are administered BID. In some cases, the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID.
  • a single dose of compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each administered once daily.
  • the therapeutically effective amount of the PD-1 inhibitor e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof
  • the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day.
  • a PD-1 inhibitor the therapeutically effective amount of the PD-1 inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the PD-1 inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day.
  • the therapeutically effective amount of the PD-1 inhibitor of the combination may be any value or subrange within the recited ranges.
  • the therapeutically effective amount of the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof) of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day.
  • the therapeutically effective amount of the PD-1 inhibitor of the combination will range between about 0.1 to about 50 mg/kg of body weight.
  • the therapeutically effective amount of the PD-1 inhibitor of the combination will range between about 10 mg/day and about 200 mg/day. In some embodiments, the therapeutically effective amount of the PD-1 inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day.
  • the therapeutically effective amount of the PD-1 inhibitor of the combination may be any value or subrange within the recited ranges.
  • the therapeutically effective amount of the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof) of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per time, and most preferably between about 0.1 to about 20 mg/kg/time.
  • the therapeutically effective amount of the PD-1 inhibitor of the combination will range between about 0.1 to about 50 mg/kg of body weight.
  • the therapeutically effective amount of the PD-1 inhibitor of the combination will range between about 10 mg/time and about 200 mg/time. In some embodiments, the therapeutically effective amount of the PD-1 inhibitor of the combination may be administered at a dose of about 10 mg/time, 20 mg/time, 30 mg/time, 40 mg/time, 50 mg/time, 60 mg/time, 70 mg/time, 80 mg/time, 90 mg/time, 100 mg/time, 110 mg/time, 120 mg/time, 130 mg/time, 140 mg/time, 150 mg/time, 160 mg/time, 170 mg/time, 180 mg/time, 190 mg/time, 200 mg/time, 240 mg/time, 480 mg/time, 600 mg/time 1000 mg/time.
  • the therapeutically effective amount of the PD-1 inhibitor of the combination may be any value or subrange within the recited ranges.
  • the time is 1 day. In some cases, the time is 7 days. In some cases, the time is 14 days. In some cases, the time is 21 days. In some cases, the time is 28 days.
  • the PD-1 inhibitor e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof
  • the compound of Formula (II) can be formulated into separate or individual dosage forms which can be co-administered one after the other.
  • the combination therapy comprises oral administration of a compound of Formula (II) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg and oral administration of a PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time).
  • the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 5 mg to about 600 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 10 mg to about 150 mg. In some embodiments, the PD-1 inhibitor is administered to a subject at about 10 mg to about 125 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 440 mg to about 520 mg. In some embodiments the PD-1 inhibitor is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the PD-1 inhibitor is administered to a subject at about 25 mg to about 100 mg.
  • the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof of is administered to a subject at about 5 mg to about 75 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 170 mg, about 190 mg, about 210 mg, about 240 mg, about 300 mg, about 350 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg,
  • the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg , about 30 mg, about 45 mg, or about 60 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 30 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 45 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 60 mg. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years.
  • the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old. [00483] In some embodiments, the PD-1 inhibitor(e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), or pharmaceutically salt thereof is administered once daily. In some embodiments, the PD-1 inhibitor(e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), is administered twice daily.
  • the PD-1 inhibitor(e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof) is administered twice daily.
  • the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), or pharmaceutically salt thereof is administered 3 times daily.
  • the PD-1 inhibitor e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof
  • the PD-1 inhibitor(e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof) is administered every other day.
  • the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), is administered every 3 days. In some embodiments, the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), is administered once a week. In some embodiments, the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), is administered every two weeks.
  • the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), is administered every 4 weeks.
  • the PD-1 inhibitor is nivolumab or a biosimilar thereof.
  • nivolumab or a biosimilar thereof is administered at a dose of 240 mg intravenously once every 2 weeks (Q2W).
  • Q2W intravenously once every 2 weeks
  • nivolumab or a biosimilar thereof is administered at a dose of 480 mg intravenously once every 4 weeks (Q4W).
  • nivolumab or a biosimilar thereof is administered intravenously over 30 minutes.
  • the PD-1 inhibitor is pembrolizumab or a biosimilar thereof. In one embodiment, pembrolizumab is administered at a dose of 200 mg intravenously once every 3 weeks (Q3W). In one embodiment, pembrolizumab or a biosimilar thereof is administered intravenously over 60 minutes.
  • the PD-1 inhibitor is cemiplimab or a biosimilar thereof. In one embodiment, cemiplimab or a biosimilar thereof is administered at a dose of 350 mg intravenously once every 3 weeks (Q3W).
  • cemiplimab or a biosimilar thereof is administered intravenously over 30 minutes.
  • the PD-1 inhibitor is tislelizumab or a biosimilar thereof.
  • tislelizumab or a biosimilar thereof is administered at a dose of 200 mg intravenously once every 3 weeks (Q3W).
  • the therapeutically effective amount of pembrolizumab or biosimilar thereof in the combination is about 350 mg administered every three weeks.
  • the PD-1 inhibitor is tislelizumab or a biosimilar thereof.
  • the therapeutically effective amount of tislelizumab, or biosimilar thereof, in the combination is about 200 mg administered every three weeks.
  • the PD-1 inhibitor is atezolizumab or a biosimilar thereof. In some cases, the therapeutically effective amount of atezolizumab or biosimilar thereof in the combination is about 1200 mg administered every three weeks.
  • the PD-1 inhibitor is the PD-L1 inhibitor is avelumab or a biosimilar thereof. In some cases, the therapeutically effective amount of avelumab or biosimilar thereof in the combination is about 10 mg/kg administered every two weeks or 800 mg every two weeks.
  • the PD-L1 inhibitor is durvalumab or a biosimilar thereof. In some cases, the therapeutically effective amount of durvalumab or biosimilar thereof in the combination is about 10 mg/kg administered every two weeks.
  • a pharmaceutical compositions comprise a PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some cases, a pharmaceutical composition comprises a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions may be used in the methods simultaneously, separately, or sequentially.
  • the pharmaceutical compositions comprise a PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), or a pharmaceutically acceptable salt thereof, and/or a compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, for use in the methods may be for simultaneous, separate or sequential use.
  • the PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered prior to administration of the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered after administration of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at about the same time as administration of the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • separate administration of each inhibitor, at different times and by different routes may be advantageous.
  • the components in the combination i.e.
  • the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and the PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof may need not be necessarily administered at essentially the same time or in any order.
  • the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at their respective MTDs.
  • the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is dosed at its MTD and the PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed in an amount less than its MTD. In some cases, the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at an amount less than its MTD and the PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD.
  • the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at less than their respective MTDs.
  • the administration can be so timed that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.
  • the PD-L1 inhibitor e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof
  • a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered QD.
  • the PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are administered BID.
  • the PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID.
  • a single dose of compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and PD-L1 inhibitor e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof
  • a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each administered once daily.
  • the therapeutically effective amount of the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof) of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day.
  • a PD-L1 inhibitor the therapeutically effective amount of the PD-L1 inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the PD-L1 inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day.
  • the therapeutically effective amount of the PD-L1 inhibitor of the combination may be any value or subrange within the recited ranges.
  • the therapeutically effective amount of the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof) of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per time, and most preferably between about 0.1 to about 20 mg/kg/time. In some embodiments, the therapeutically effective amount of the PD-L1 inhibitor of the combination will range between about 0.1 to about 50 mg/kg of body weight. In some embodiments, the therapeutically effective amount of the PD-L1 inhibitor of the combination will range between about 10 mg/time and about 200 mg/time.
  • the PD-L1 inhibitor e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof
  • the therapeutically effective amount of the PD-L1 inhibitor of the combination may be administered at a dose of about 10 mg/time, 20 mg/time, 30 mg/time, 40 mg/time, 50 mg/time, 60 mg/time, 70 mg/time, 80 mg/time, 90 mg/time, 100 mg/time, 110 mg/time, 120 mg/time, 130 mg/time, 140 mg/time, 150 mg/time, 160 mg/time, 170 mg/time, 180 mg/time, 190 mg/time, 200 mg/time, 240 mg/time, 300 mg/time, 480 mg/time.
  • the therapeutically effective amount of the PD-L1 inhibitor of the combination may be any value or subrange within the recited ranges. In some cases, the time is 1 day.
  • the time is 7 days. In some cases, the time is 14 days. In some cases, the time is 21 days. In some cases, the time is 28 days. [00498]
  • the PD-L1 inhibitor e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof
  • the compound of Formula (II), or a pharmaceutically acceptable salt thereof can be formulated into separate or individual dosage forms which can be co-administered one after the other. Another option is that if the route of administration is the same (e.g.
  • the combination therapy comprises oral administration of a compound of Formula (II) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg and oral administration of a PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time).
  • the PD-L1 inhibitor is administered to a subject at about 200 mg to about 500 mg.
  • PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 440 mg to about 520 mg. In some embodiments PD-L1 inhibitor is administered to a subject at about 10 mg to about 100 mg. In some embodiments, PD-L1 inhibitor is administered to a subject at about 240 mg to about 480 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof of is administered to a subject at about 5 mg to about 75 mg.
  • the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 170 mg, about 190 mg, about 210 mg, about 240 mg, about 300 mg, about 350 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 540 mg, about 580 mg, or about 650 mg.
  • the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg , about 30 mg, about 45 mg, or about 60 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 30 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 240 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 480 mg. In some embodiments, the subject is between 12 years old to 18 years old.
  • the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.
  • the PD-L1 inhibitor e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof
  • the PD-L1 inhibitor is administered twice daily.
  • the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), or pharmaceutically salt thereof is administered 3 times daily. In some embodiments, the PD-L1 inhibitor(e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), is administered once weekly. In some embodiments, the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), is administered every other day.
  • the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), is administered every 3 days. In some embodiments, the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), is administered once a week. In some embodiments, the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), is administered every two weeks.
  • the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), is administered every 4 weeks.
  • the PD-L1 inhibitor is avelumab or a biosimilar thereof.
  • avelumab or a biosimilar thereof is administered intravenously in the amount of about 800 mg every 2 weeks (Q2W) or about 10 mg/kg every 2 weeks (Q2W).
  • avelumab or a biosimilar thereof is administered intravenously over 60 minutes.
  • the PD-L1 inhibitor is atezolizumab or a biosimilar thereof.
  • Atezolizumab or a biosimilar thereof is administered at a dose of 1200 mg intravenously once every 3 weeks (Q3W) or at a dose of 840 mg intravenously two weeks apart. In some cases, atezolizumab or a biosimilar thereof is administered intravenously over 60 minutes.
  • the PD-L1 inhibitor is durvalumab or a biosimilar thereof. In one embodiment, durvalumab or a biosimilar thereof is administered at a dose of 10 mg/kg intravenously once every 2 weeks (Q2W). In one embodiment, durvalumab or a biosimilar thereof is administered intravenously over 60 minutes.
  • a pharmaceutical composition comprises a CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprises a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions may be used in the methods simultaneously, separately, or sequentially.
  • the pharmaceutical compositions comprising a CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, and/or a compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, for use in the methods may be for simultaneous, separate or sequential use.
  • the CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered prior to administration of the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered after administration of the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at about the same time as administration of the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • each inhibitor at different times and by different routes, may be advantageous.
  • the components in the combination i.e. compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof and the CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, need not be necessarily administered at essentially the same time or in any order.
  • the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at their respective MTDs.
  • the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is dosed at its MTD and the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed in an amount less than its MTD. In some cases, the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at an amount less than its MTD and the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD.
  • the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at less than their respective MTDs. In some cases, the administration can be so timed that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.
  • the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered QD. In some cases, the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are administered BID. In some cases, the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID.
  • a single dose of compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each administered once daily.
  • the therapeutically effective amount of the CTLA-4 inhibitor of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day. In some embodiments, the therapeutically effective amount of the CTLA-4 inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the CTLA-4 inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day.
  • the therapeutically effective amount of the CTLA-4 inhibitor of the combination may be any value or subrange within the recited ranges.
  • the therapeutically effective amount of the CTLA-4 inhibitor of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day. In some embodiments, the therapeutically effective amount of the CTLA-4 inhibitor of the combination will range between about 0.1 to about 50 mg/kg of body weight. In some embodiments, the therapeutically effective amount of the CTLA- 4 inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the CTLA-4 inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day.
  • the therapeutically effective amount of the CTLA-4 inhibitor of the combination may be any value or subrange within the recited ranges.
  • the CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, and the compound of Formula (II), or a pharmaceutically acceptable salt thereof can be formulated into separate or individual dosage forms which can be co-administered one after the other.
  • the route of administration is the same (e.g. oral) two active compounds can be formulated into a single form for co-administration, both methods of co-administration, however, being part of the same therapeutic treatment or regimen.
  • the combination therapy comprises oral administration of a compound of Formula (II) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg and oral administration of a CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time).
  • the CTLA-4 inhibitor is administered to a subject at about 200 mg to about 500 mg.
  • the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 440 mg to about 520 mg.
  • the CTLA-4 inhibitor is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the CTLA-4 inhibitor is administered to a subject at about 240 mg to about 480 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof of is administered to a subject at about 5 mg to about 75 mg.
  • the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 170 mg, about 190 mg, about 210 mg, about 240 mg, about 300 mg, about 350 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 540 mg, about 580 mg, or about 650 mg.
  • the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg , about 30 mg, about 45 mg, or about 60 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 30 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 240 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 480 mg. In some embodiments, the subject is between 12 years old to 18 years old.
  • the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old. [00513] In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered once daily. In some embodiments, the CTLA-4 inhibitor, is administered twice daily. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered 3 times daily. In some embodiments, the CTLA-4 inhibitor, is administered once weekly. In some embodiments, the CTLA-4 inhibitor, is administered every other day. In some embodiments, the CTLA-4 inhibitor, is administered every 3 days. In some embodiments, the CTLA-4 inhibitor, is administered once a week.
  • the CTLA-4 inhibitor is administered every two weeks. In some embodiments, the CTLA-4 inhibitor, is administered every 4 weeks. KRAS Inhibitor Dosing [00514] In some embodiments, a single dose of compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is administered per day (i.e., in about 24 hour intervals) (i.e., QD). In some cases, two doses of the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are administered per day (i.e., BID).
  • the present disclosure provides methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the cancer is a KRas G12D-associated cancer.
  • the cancer is a KRas G12V-associated cancer.
  • the cancer is a KRas wildtype-associated cancer.
  • the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer.
  • the cancer is a solid tumor cancer.
  • the cancer is a solid tumor cancer with a KRAS mutation. In some cases, the cancer is a solid tumor cancer with KRAS wildtype. In some cases, the cancer is a solid tumor cancer with a G12D mutation. In some cases, the cancer is a solid tumor cancer with a G12V mutation. In some cases, the cancer is a KRAS wildtype-associated cancer. In some cases, the KRas G12D-associated cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer. In some cases, the compound of Formula (II) is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof.
  • the compound of Formula (II) is compound 53. In some cases, the compound of Formula (II) is compound 61. In some cases, the compound of Formula (II) is compound 63. In some cases, the compound of Formula (II) is compound 64. In some cases, the compound of Formula (II) is compound 69. In some cases, the compound of Formula (II) is compound 96.
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (II) selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the compound of Formula (II) is compound 53.
  • the compound of Formula (II) is compound 61.
  • the compound of Formula (II) is compound 63.
  • the compound of Formula (II) is compound 64.
  • the compound of Formula (II) is compound 69.
  • the compound of Formula (II) is compound 96.
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a combination of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (II) selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the compound of Formula (II) is compound 53.
  • the compound of Formula (II) is compound 61.
  • the compound of Formula (II) is compound 63.
  • the compound of Formula (II) is compound 64.
  • the compound of Formula (II) is compound 69. In some cases, the compound of Formula (II) is compound 96. [00519] In an aspect the present disclosure provides methods for increasing the sensitivity of a cancer cell to a compound or salt of Formula (II), comprising contacting the cancer cell with an effective amount of a combination of a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the immunomodulator inhibitor synergistically increases the sensitivity of the cancer cell to the compound or salt of Formula (II).
  • the contacting is in vitro. In one embodiment, the contacting is in vivo.
  • the present disclosure provides methods of inhibiting KRas G12 mutants or wildtype in a subject comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the method may inhibit KRas G12 mutants or wildtype activity in a cell.
  • inhibiting KRas G12 mutants or wildtype activity in a cell may include contacting the cell in which inhibition of KRas G12 mutants or wildtype activity is desired with an effective amount of a compound of Formula (II), or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof and an immunomodulator inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • a cell in which inhibition of KRas G12 mutants or wildtype activity is desired is contacted with an effective amount of a compound of Formula (II) or pharmaceutically acceptable salt of any one thereof and an immunomodulator inhibitor to negatively modulate the activity of KRas G12 mutants or wildtype.
  • the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12 mutants or wildtype activity within the cell.
  • the cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12 mutants or wildtype.
  • the ability of compounds to bind KRas G12 mutants or wildtype may be monitored in vitro using well known methods.
  • the inhibitory activity of compounds of Formula (II) and an immunomodulator inhibitor in cells may be monitored, for example, by measuring the inhibition of KRas G12 mutants or wildtype activity of the amount of phosphorylated ERK.
  • the present disclosure provides methods of reprogramming a tumor microenvironment (TME) of a subject in favor of antitumor immunity, wherein reprogramming includes modulating tumor cell cytokine/chemokine release in the tumor microenvironment of the subject.
  • the method includes providing a compound described herein (a compound of Formula (II), e.g., a compound selected from compounds 53, 61, 63, 64, 69, and 96).
  • the method also includes providing an immunomodulator (e.g., checkpoint inhibitors (inhibitors targeting: cytotoxic T lymphocyte associated antigen 4 (CTLA-4), e.g. Yervoy/lpilimumab; programmed death 1/programmed death-ligand 1 (PD-1/PD-L1), e.g. Keytruda/pembrolizumab; and lymphocyte-activation gene 3 (LAG-3), e.g. BMS-986016/relatlimab)).
  • CTLA-4 cytotoxic T lymphocyte associated antigen 4
  • PD-1/PD-L1 programmed death 1/programmed death-ligand 1
  • LAG-3 lymphocyte-activation gene 3
  • the method can also include providing a compound of Formula (II) and an immunomodulator in combination (sequentially or simultaneously).
  • the subject has a KRas-associated cancer.
  • the present disclosure provides methods of treating a KRas G12D- associated cancer in a subject in need thereof, comprising administering to the subject a combination of an immunomodulator, and a compound of Formula (II) or a pharmaceutically acceptable salt thereof.
  • Formula (II) is Formula (II*).
  • the compound is selected from compounds 53, 61, 63, 64, 69, and 96.
  • the present disclosure provides methods of treating a KRas G12V- associated cancer in a subject in need thereof, comprising administering to the subject a combination of an immunomodulator, and a compound of Formula (II) or a pharmaceutically acceptable salt thereof.
  • Formula (II) is Formula (II*).
  • the compound is selected from compounds 53, 61, 63, 64, 69, and 96.
  • methods of treating cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided and an immunomodulator inhibitor.
  • compositions and methods provided herein may be used for the treatment of a KRas G12 mutants or wildtype-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (II), a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and an immunomodulator inhibitor are provided.
  • the KRas G12 mutants or wildtype associated cancer is lung cancer.
  • the KRas G12 mutants or wildtype associated cancer is solid tumor cancer.
  • the KRs G12 mutants are selected from G12D and G12V.
  • the KRas G12 mutants is G12D.
  • the KRas G12 mutants is G12V.
  • the synergistic increase in potency of the compound or salt of Formula (II) results in an improved efficacy of the compound or salt of Formula (II).
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer.
  • the cancer is a solid tumor cancer.
  • the cancer is a solid tumor cancer with a KRAS mutation.
  • the cancer is a KRas wildtype-associated cancer.
  • the cancer is a KRas G12D-associated cancer. In one embodiment, the cancer is a KRas G12V-associated cancer. In one embodiment, the cancer is a KRas wildtype-associated cancer. In some cases, the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer. In some cases, the cancer is a solid tumor cancer. In some cases, the cancer is a solid tumor cancer with a KRas mutation. In some cases, the cancer is a solid tumor cancer with KRas wildtype. In some cases, the cancer is a solid tumor cancer with a G12D mutation. In some cases, the cancer is a solid tumor cancer with a G12V mutation.
  • the cancer is a KRas wildtype-associated cancer.
  • the KRas G12D-associated cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer.
  • the compound of Formula (II) is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof.
  • the compound of Formula (II) is compound 53.
  • the compound of Formula (II) is compound 61.
  • the compound of Formula (II) is compound 63.
  • the compound of Formula (II) is compound 64.
  • the compound of Formula (II) is compound 69.
  • the compound of Formula (II) is compound 96.
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (II) selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the compound of Formula (II) is compound 53.
  • the compound of Formula (II) is compound 61.
  • the compound of Formula (II) is compound 63.
  • the compound of Formula (II) is compound 64.
  • the compound of Formula (II) is compound 69. In some cases, the compound of Formula (II) is compound 96. [00531] In an aspect the present disclosure provides methods for increasing the sensitivity of a cancer cell to a compound or salt of Formula (II), comprising contacting the cancer cell with an effective amount of a combination of a compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the PD-1 inhibitor synergistically increases the sensitivity of the cancer cell to the compound or salt of Formula (II).
  • the contacting is in vitro. In one embodiment, the contacting is in vivo.
  • the present disclosure provides methods of inhibiting KRas G12 mutants in a subject comprising administering to the subject a therapeutically effective amount of a combination of a PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (II),or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the method may inhibit KRas G12 mutants or wildtype activity in a cell.
  • inhibiting KRas G12 mutants or wildtype activity in a cell may include contacting the cell in which inhibition of KRas G12 mutants or wildtype activity is desired with an effective amount of a compound of Formula (II), or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt of any one thereof and a PD-1 inhibitor.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • a cell in which inhibition of KRas G12 mutants or wildtype activity is desired is contacted with an effective amount of a compound of Formula (II), or pharmaceutically acceptable salt of any one thereof and a PD-1 inhibitor to negatively modulate the activity of KRas G12 mutants or wildtype.
  • the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12 mutants or wildtype activity within the cell.
  • the cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12 mutants or wildtype.
  • the ability of compounds to bind KRas G12 mutants or wildtype may be monitored in vitro using well known methods.
  • the inhibitory activity of exemplary compounds and a PD-1 inhibitor in cells may be monitored, for example, by measuring the inhibition of KRas G12 mutants or wildtype activity of the amount of phosphorylated ERK.
  • methods of treating cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound or salt of Formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided and a PD-1 inhibitor.
  • compositions and methods provided herein may be used for the treatment of a KRas G12 mutants or wildtype -associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (II), a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a PD-1 inhibitor are provided.
  • the KRas G12 mutants or wildtype associated cancer is lung cancer.
  • compositions and methods provided herein may be used for the treatment of a KRas G12D-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (II), a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a PD-1 inhibitor are provided.
  • the method of treating a cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of a PD-1 inhibitor and a compound or salt of Formula (II), synergistically increases the potency of the compound or salt of Formula (II).
  • the synergistic increase in potency of the compound or salt of Formula (II) results in an improved efficacy of the compound or salt of Formula (II).
  • PD-L1 inhibitor combination therapy [00538]
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer.
  • the cancer is a solid tumor cancer.
  • the cancer is a solid tumor cancer with a KRas mutation. In some cases, the cancer is a KRAS wildtype-associated cancer. In one embodiment, the cancer is a KRas G12D-associated cancer. In one embodiment, the cancer is a KRas G12V-associated cancer. In one embodiment, the cancer is a KRas wildtype-associated cancer. In some cases, the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer. In some cases, the cancer is a solid tumor cancer. In some cases, the cancer is a solid tumor cancer with a KRAS mutation. In some cases, the cancer is a solid tumor cancer with KRAS wildtype.
  • the cancer is a solid tumor cancer with a G12D mutation. In some cases, the cancer is a solid tumor cancer with a G12V mutation. In some cases, the cancer is a KRAS wildtype-associated cancer. In some cases, the KRas G12D-associated cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer.
  • the compound of Formula (II) is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof. In some cases, the compound of Formula (II) is compound 53. In some cases, the compound of Formula (II) is compound 61. In some cases, the compound of Formula (II) is compound 63.
  • the compound of Formula (II) is compound 64. In some cases, the compound of Formula (II) is compound 69. In some cases, the compound of Formula (II) is compound 96. [00539] In an aspect the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (II) selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. In some cases, the compound of Formula (II) is compound 53. In some cases, the compound of Formula (II) is compound 61.
  • the compound of Formula (II) is compound 63. In some cases, the compound of Formula (II) is compound 64. In some cases, the compound of Formula (II) is compound 69. In some cases, the compound of Formula (II) is compound 96.
  • the present disclosure provides methods for increasing the sensitivity of a cancer cell to a compound or salt of Formula (II), comprising contacting the cancer cell with an effective amount of a combination of a compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the PD-L1 inhibitor synergistically increases the sensitivity of the cancer cell to the compound or salt of Formula (II).
  • the contacting is in vitro. In one embodiment, the contacting is in vivo.
  • the present disclosure provides methods of inhibiting KRas G12 mutants or wildtype in a subject comprising administering to the subject a therapeutically effective amount of a combination of a PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (II),or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the method may inhibit KRas G12 mutants or wildtype activity in a cell.
  • inhibiting KRas G12 mutants or wildtype activity in a cell may include contacting the cell in which inhibition of KRas G12 mutants or wildtype activity is desired with an effective amount of a compound of Formula (II), or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt of any one thereof and a PD-L1 inhibitor.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • a cell in which inhibition of KRas G12 mutants or wildtype activity is desired is contacted with an effective amount of a compound of Formula (II) or pharmaceutically acceptable salt of any one thereof and an PD-L1 inhibitor to negatively modulate the activity of KRas G12 mutants or wildtype.
  • the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12 mutants or wildtype activity within the cell.
  • the cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12 mutants or wildtype.
  • the ability of compounds to bind KRas G12 mutants or wildtype may be monitored in vitro using well known methods.
  • the inhibitory activity of exemplary compounds and an PD-L1 inhibitor in cells may be monitored, for example, by measuring the inhibition of KRAS G12 mutants and wildtype activity of the amount of phosphorylated ERK.
  • methods of treating cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound or salt of Formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided and an PD-L1 inhibitor.
  • compositions and methods provided herein may be used for the treatment of a KRas G12 mutants or wildtype-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (II), a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a PD-L1 inhibitor are provided.
  • the KRas G12 mutants or wildtype associated cancer is lung cancer.
  • the method of treating a cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of a PD-L1 inhibitor and a compound or salt of Formula (II), synergistically increases the potency of the compound or salt of Formula (II).
  • the synergistic increase in potency of the compound or salt of Formula (II) results in an improved efficacy of the compound or salt of Formula (II).
  • CTLA-4 inhibitor combination therapy [00546]
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer.
  • the cancer is a solid tumor cancer.
  • the cancer is a solid tumor cancer with a KRAS mutation.
  • the cancer is a KRAS wildtype-associated cancer.
  • the cancer is a KRas G12D- associated cancer. In one embodiment, the cancer is a KRas G12V-associated cancer. In one embodiment, the cancer is a KRas wildtype-associated cancer. In some cases, the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer. In some cases, the cancer is a solid tumor cancer. In some cases, the cancer is a solid tumor cancer with a KRAS mutation. In some cases, the cancer is a solid tumor cancer with KRAS wildtype. In some cases, the cancer is a solid tumor cancer with a G12D mutation. In some cases, the cancer is a solid tumor cancer with a G12V mutation.
  • the cancer is a KRAS wildtype-associated cancer.
  • the KRas G12D-associated cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer.
  • the compound of Formula (II) is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof.
  • the compound of Formula (II) is compound 53.
  • the compound of Formula (II) is compound 61.
  • the compound of Formula (II) is compound 63.
  • the compound of Formula (II) is compound 64.
  • the compound of Formula (II) is compound 69.
  • the compound of Formula (II) is compound 96.
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (II) selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the compound of Formula (II) is compound 53.
  • the compound of Formula (II) is compound 61.
  • the compound of Formula (II) is compound 63.
  • the compound of Formula (II) is compound 64.
  • the compound of Formula (II) is compound 69. In some cases, the compound of Formula (II) is compound 96. [00548] In an aspect the present disclosure provides methods for increasing the sensitivity of a cancer cell to a compound or salt of Formula (II), comprising contacting the cancer cell with an effective amount of a combination of a compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the CTLA-4 inhibitor synergistically increases the sensitivity of the cancer cell to the compound or salt of Formula (II).
  • the contacting is in vitro. In one embodiment, the contacting is in vivo.
  • the present disclosure provides methods of inhibiting KRas G12 mutants or wildtype in a subject comprising administering to the subject a therapeutically effective amount of a combination of a CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the method may inhibit KRas G12 mutants or wildtype activity in a cell.
  • inhibiting KRas G12 mutants or wildtype activity in a cell may include contacting the cell in which inhibition of KRas G12 mutants activity is desired with an effective amount of a compound of Formula (II), or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt of any one thereof and a CTLA-4 inhibitor.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • a cell in which inhibition of KRas G12 mutants or wildtype activity is desired is contacted with an effective amount of a compound of Formula (II), or pharmaceutically acceptable salt of any one thereof and a CTLA-4 inhibitor to negatively modulate the activity of KRas G12 mutants or wildtype.
  • the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12 mutants or wildtype activity within the cell.
  • the cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12 mutants or wildtype.
  • the ability of compounds to bind KRas G12 mutants or wildtype may be monitored in vitro using well known methods.
  • the inhibitory activity of exemplary compounds and a CTLA-4 inhibitor in cells may be monitored, for example, by measuring the inhibition of KRas G12 mutants or wildtype activity of the amount of phosphorylated ERK.
  • methods of treating cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound or salt of Formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided and a CTLA-4 inhibitor.
  • compositions and methods provided herein may be used for the treatment of a KRas G12 mutants or wildtype-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (II), a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a CTLA-4 inhibitor are provided.
  • KRas G12 mutants or wildtype associated cancer is lung cancer.
  • compositions and methods provided herein may be used for the treatment of a KRas G12D-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (II), a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a CTLA-4 inhibitor are provided.
  • the method of treating a cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of a CTLA-4 inhibitor and a compound or salt of Formula (II), synergistically increases the potency of the compound or salt of Formula (II).
  • the synergistic increase in potency of the compound or salt of Formula (II) results in an improved efficacy of the compound or salt of Formula (II).
  • the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • contacting a KRas G12 mutants or wildtype with a compound provided herein and an immunomodulator inhibitor includes the administration of the compound provided herein and an immunomodulator inhibitor to an individual or patient, such as a human, having KRas G12D and/or other G12 mutants, as well as, for example, introducing a compound provided herein and an immunomodulator inhibitor into a sample containing a cellular or purified preparation containing the KRas G12D and/or other G12 mutants.
  • the compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc.
  • cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinom
  • the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer. In some cases, the cancer is non-small cell lung cancer. In some cases, the cancer is a solid tumor cancer.
  • the concentration and route of administration to the patient will vary depending on the cancer to be treated.
  • the compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co- administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.
  • the compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions.
  • compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof in therapeutically effective amounts to said subject.
  • compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose.”
  • prophylactically effective amount or dose In this use, the precise amounts also depend on the patient's state of health, weight, and the like.
  • effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • a maintenance dose is administered if necessary.
  • the dosage or the frequency of administration, or both can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.02 - about 5000 mg per day, in some embodiments, about 1 – about 1500 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compound.
  • the unit dosage may be in the form of a package containing discrete quantities of the formulation.
  • Non- limiting examples are packaged tablets or capsules, and powders in vials or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.
  • multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition.
  • formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.
  • Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD 50 (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 the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED 50 .
  • the invention provides a method of treating or preventing a disease, state or condition in a patient in need thereof comprising administering to the patient an effective amount of a compound of any one of embodiments of the invention or a pharmaceutically acceptable salt thereof.
  • the disease, state or condition may be selected from a group as described elsewhere herein.
  • compounds herein can adopt to selectively eliminate an over activated KRas signaling which is induced by KRas mutations by directly binding with the mutated KRas protein, either by stabilizing its GDP bound form (the inactive form) or by blocking the interaction between GTP bound form and its downstream target protein.
  • another way is to hijack the protein degradation mechanism in a cell and leverage E3 ligases’ (like VHL, CRBN or IAPs) substrate specificity through a bi-functional molecule called Proteolysis targeting chimera (PROTAC) (Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe- Paganon S, Bradner JE.
  • DRUG DEVELOPMENT Phthalimide conjugation as a strategy for in vivo target protein degradation. Science.2015 Jun 19; 348 (6241): 1376-81), which can bind with both mutated KRas protein and E3 ligase, create interactions between those two proteins and induce KRas degradation.
  • a target protein i.e., KRAS G12D
  • E3 ubiquitin ligase-binding moiety which may induce proteasome- mediated degradation of selected proteins.
  • the bifunctional compound comprises a target protein (i.e., KRAS G12D)-binding moiety and an E3 ubiquitin ligase-binding moiety known in the art.
  • a target protein i.e., KRAS G12D
  • E3 ubiquitin ligase-binding moiety known in the art.
  • disclosed herein is the use of the compound disclosed herein in the preparation of degrading a target protein compound by using chemical modification of the compound disclosed herein.
  • the target protein-binding moiety is derived from a compound of Formula (I), Formula (II), Formula (II*), or Formula (III).
  • the compounds of the present disclosure can generally be prepared in a number of ways well known to those skilled in the art of organic synthesis.
  • IA-b can be formed by addition of a solution of a ketone in THF at -78 ⁇ C and the reaction is quenched at -78 ⁇ C.
  • Ester IA-b can be reduced by DIBAL or LiAlH 4 to diol IA-c, which can be cyclized into IA-d via Mitsunobu reaction or in the presence of BuLi and TsCl in THF at -78 ⁇ C.
  • Compound I can be prepared via Pd mediated coupling reactions or in the presence of a base such as NaH or LiHMDS.
  • Ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate can be deprotonated with LDA or LiHMDS at -78 ⁇ C in THF.
  • IB-a can be formed by addition of a solution of a ketone in THF at -78 ⁇ C and the reaction is quenched at -78 ⁇ C.
  • Ester IB-a can be reduced by DIBAL or LiAlH 4 to diol IB-b, which can be cyclized into IB-c via Mitsunobu reaction or in the presence of BuLi and TsCl in THF at -78 ⁇ C.
  • IB-d Treatment of R1 with IB-c can afford IB-d in the presence of a base such as DIEA in DCM can afford IB-d, which can be oxidized to sulfone IB-e.
  • Compound I can be prepared via Pd mediated coupling reactions or in the presence of a base such as NaH or LiHMDS.
  • Scheme IIA Treatment of t-Butyl-sulfinimade and a ketone in the presence of Ti(OEt) 4 can afford IIA-a.
  • a solution of IIA-a in THF can be added to a solution of IA-a, deprotonated with LDA or LiHMDS at -78 ⁇ C in THF, and the reaction can be quenched at -78 ⁇ C to afford IIA-b.
  • Ester IIA- b can be reduced by DIBAL or LiAlH4 to IIA-c, which can be cyclized into IIA-d via a sequence of removal of sufinimade under HCl, chorination of OH and cyclization in the presence of a base such as NaOH (ref. Garcia, D.; Moreno, B.; Soler, T.; Foubelo, F.; Yus, M. Tetrahedron Lett.2009, 50, 4710).
  • a base such as NaOH
  • R3 of IIA-e can be introduced via reductive amination or alkylation.
  • Compound II can be prepared via Pd mediated coupling reactions or in the presence of a base such as NaH or LiHMDS.
  • Scheme IIB [00576] Ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate can be deprotonated with LDA or LiHMDS at -78 ⁇ C in THF.
  • IIB-a can be formed by addition of a solution of IIA-a in THF at -78 ⁇ C and the reaction is quenched at -78 ⁇ C.
  • Ester IIB-a can be reduced by DIBAL or LiAlH4 to diol IIB-b, which can be cyclized into IIB-c as described in Scheme IIA above.
  • R3 of IIB-d can be introduced via reductive amination or alkylation.
  • Treatment of R1 with IIB-d can afford IIB-e in the presence of a base such as DIEA in DCM.
  • IIB-e can be oxidized to sulfoxide IIB-f, which can be converted to II in the presence of a base such as NaH or LiHMDS.
  • Example 1 Exemplary synthesis of 4'-(azepan-1-yl)-4-chloro-2'-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydrospiro[indene-1,7'-pyrano[4,3- d]pyrimidine] (compound 1) [00577] Step 1: To a solution of methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate (1.0 g, 4.52 mmol, 1.0 eq) in ACN (7 mL) was added DIPEA (1.17 g, 9.05 mmol, 2.0 eq) and azepane (449 mg, 4.52 mmol, 1.0 eq) at 20 °C.
  • Step 2 To a solution of LDA (2 M, 2.11 mL, 1.2 eq) in THF (30 mL) was added compound 1a (1.0 g, 3.52 mmol, 1.0 eq) at -60°C. The mixture was stirred at -60 °C for 30 mins. 4-Chloro-2,3-dihydro-1H-inden-1-one (587 mg, 3.52 mmol, 1.0 eq) was added at -60 °C.
  • Step 3 To a solution of compound 1b (490 mg, 1.09 mmol, 1.0 eq) in DCM (5 mL) was added DIBAL-H (1 M, 3.26 mL, 3.0 eq) at 0 °C. Then the reaction was stirred at 0 °C for 1 hr. The reaction mixture was quenched by H 2 O (20 ml) at 25°C. The mixture was extracted with DCM (10 mL * 2). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • Step 5 To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methanol (37.8 mg, 237 umol, 1.2 eq) in THF (2 mL) was added NaH (15.8 mg, 396 umol, 60% purity, 2.0 eq) at 0 °C. The reaction was stirred at 0 °C for 30 min. Then a solution of compound 1d (80 mg, 198 umol, 1.0 eq) in THF (0.5 mL) was added to the above solution at 0 °C. The reaction was continued to stir at 60 °C for 8 hrs.
  • Step 3 Synthesis of tert-butyl 3-[6-[(4-chloro-1-hydroxy-indan- 1-yl)methyl]-2- [[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5-methoxycarbonyl- pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2c).
  • Step 1 Synthesis of 4-hydrazono-2,4-dihydroindeno[1,2-c]pyrazole (3a). To a solution of indane-1,3-dione (5.00 g, 34.2 mmol, 1.0 eq) in THF (50 mL) was added DMF-DMA (4.15 g, 34.9 mmol, 1.02 eq) dropwise. The resulting mixture was stirred at ⁇ room temperature ⁇ for 1 h. TLC showed SM was consumed.
  • Step 4 Synthesis of 2-(2-trimethylsilylethoxymethyl)indeno[1,2-c]pyrazol-4-one (3d).
  • 2H-indeno[1,2-c]pyrazol-4-one 800 mg, 4.70 mmol, 1.0 eq
  • DMF 12 mL
  • NaH 169 mg, 7.05 mmol, 1.5 eq
  • SEMCl 1.17 g, 7.05 mmol, 1.5 eq
  • Step 7 Synthesis of tert-butyl (1R,5S)-3-[2-chloro-2'-(2- trimethylsilylethoxymethyl)spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,4'-indeno[1,2- c]pyrazole]-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3g).
  • Step 9 Synthesis of 4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5',8'-dihydro-2H-spiro[indeno[1,2- c]pyrazole-4,7'-pyrano[4,3-d]pyrimidine] (3).
  • Step 2 Synthesis of 2-(1-(4-chloro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydrospiro[indene-1,7'-pyrano[4,3-d]pyrimidin]-4'-yl)azepan- 4-ylidene)acetonitrile (19a).
  • Example 8 Exemplary synthesis of syn-1-[4'-chloro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'- indane]-4-yl]azepane- [00630] To a mixture of 4'-chloro-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl] methoxy]-4-(2,3,6,7-tetrahydroazepin-1-yl)spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'- indane] (18, 50.0 mg, 0.1 mmol) in acetone (0.3 mL) and water (0.1 mL) were added K 2 O
  • Step 1 Synthesis of ethyl 4-chloro-6-((4-chloro-1-hydroxy-2,3-dihydro-1H-inden-1- yl)methyl)-2-(methylthio)pyrimidine-5-carboxylate (23a).
  • a solution of LiHMDS (1 M, 24.3 mL, 2.0 eq) in THF (10 mL) was added a solution of Ethyl 4-chloro-6-methyl-2- (methylthio)pyrimidine-5-carboxylate (3.0 g, 12.2 mmol, 1.0 eq) in THF (10 mL) at -60 °C. Then the reaction was stirred at -60 °C for 30 minutes.
  • Step 4 Synthesis of (3R)-1-(4'-chloro-2-methylsulfanyl-spiro[5,8-dihydropyrano[4,3- d]pyrimidine-7,1'-indane]-4-yl)-3-methyl-piperidin-3-ol (23d).
  • Example 10 Exemplary synthesis of 2'-amino-4-(azepan-1-yl)-2-[[rac-(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine- 7,4'-6,7-dihydro-5H-benzothiophene]-3'-carbonitrile (Compound 26) [00642] Step 1.
  • Step 5 Synthesis of 4-(azepan-1-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,2'-cyclohexane]- 1'-one (26e).
  • Compound 24A (5*)-9-[(7*)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 1,3,9-triazaspiro[4.5]decane-2,4-dione [00651] Compound 24 was purified on an DAICELCHIRALCEL®AD (250*25 mm 10 um) column on a Waters SFC 150 system (Mobile Phase A:Supercritical CO2, Mobile Phase B:IPA (+0.1% 7.0mol/l Ammonia in MeOH); A:B: 60:40; Flow: 70ml/min) to give 3 peaks and the fastest eluting P1 was assigned to compound 24A.
  • DAICELCHIRALCEL®AD 250*25 mm 10 um
  • Example 11 Exemplary synthesis of 5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (compound 27A) and 5-[(7R)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,
  • Step 1.27B-a (140.mg, 0.4mmol), N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide;hydrochloride (165.07mg, 0.79mmol) and DIEA (0.21mL, 1.19mmol) in DMF (2mL) was stirred at 100 °C for 2 h. The mixture was concentrated.
  • Acetic acid (0.03mL, 0.55mmol) was added the reaction mixture to quench the reaction.
  • the crude product was purified by Prep-HPLC (eluted with CH 3 CN in H 2 O (0.1% FA) from 5.0% to 95%) to get 5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide;formic acid 27B (67.2 mg, 0.1052 mmol, 56.92% yield) was obtained as white solid.
  • Example 12 Exemplary synthesis of (7S)-4-(azepan-1-yl)-4'-chloro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-indane] (28A) [00658] Step 1.
  • reaction mixture was poured into water (50 mL), the aqueous phase was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • Step 3 Synthesis of (S)-4'-(azepan-1-yl)-2',4-dichloro-2,3,5',8'-tetrahydro-6'H- spiro[indene-1,7'-pyrido[4,3-d]pyrimidine] (28A-d).
  • 28A-d a solution of compound 28A-c (0.2 g, 4.58 mmol) in HCl/dioxane (4 M, 2 mL) at 0 °C. The mixture was stirred at 0 °C for 3 hrs. The reaction mixture was adjusted pH to 8 by NaHCO3 and extracted with EtOAc (5 mL x 2).
  • Step 1 To a solution of 7-hydroxytetralin-1-one (30000.mg, 184.97mmol) in DMF (200mL) was added K2CO3 (51128.92mg, 369.94mmol) at rt, then BnBr (34798.63mg, 203.47mmol) was added. The mixture was stirred at rt for 16h. Then the mixture was extracted with EtOAc/H 2 O. The combined organic layer was washed with brine, dried over Na 2 SO 4 and concentrated. The obtained solid is triturated in MeOH and then filtered.
  • K2CO3 51128.92mg, 369.94mmol
  • BnBr 34798.63mg, 203.47mmol
  • Step 2.7-benzyloxytetralin-1-one (39a) (4320.mg, 17.12mmol), (S)-2- methylpropane-2-sulfinamide (2905.23mg, 23.97mmol) and Ti(IV) ethoxide (10.mL, 51.37mmol) were mixed and stirred under argon at rt.
  • the reaction vessel was placed into the microwave reactor and heated to 100 °C for 120 min.
  • Step 4 The mixture of ethyl 2-[7-benzyloxy-1-[[(S)-tert-butylsulfinyl]amino]tetralin- 1-yl]acetate (39c) (1200.mg, 2.71mmol) and HCl in dioxane (5.mL, 20.mmol) in Ethanol (10mL) was stirred at rt for 1 h.
  • reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 3% to 7% MeOH/DCM) to afford 5-(7'-benzyloxy-2-chloro-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-tetralin]-4-yl)-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine- 2-carboxamide (39k) (25mg,0.041mmol, 64% yield) as a white solid.
  • reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure.
  • the mixture was purified by flash column chromatography (silica gel, eluting with 0% to 10% MeOH/DCM) to afford 5-[7'-benzyloxy-6- methyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8- dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (39l) (25mg,0.034mmol, 83% yield) as a white solid.
  • Example 15 Exemplary synthesis of 5-[6'-(difluoromethoxy)-2-[[rac-(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine- 7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (41) [00702] To a solution of 5-[6'-hydroxy-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- N,
  • Step 2 The mixture of [3-chloro-5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-thiomorpholino-methanone (52a) (25.mg, 0.03mmol), Iodobenzene Diacetate (23.21mg, 0.07mmol) and Ammonium acetate (4.23mg, 0.05mmol) in Methanol (3mL) was stirred at 25 °C for 2 h.
  • Step 10 The mixture of 3-chloro-5-[(7S)-2,4'-dichloro-6-methyl-spiro[5,8- dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (53i) (20.0 mg, 0.036 mmol), [(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (7.38 mg, 0.046 mmol), Cs2CO3 (29.06 mg, 0.089 mmol), Pd 2 dba 3 (3.27 mg, 0.00
  • Example 19 Exemplary synthesis of 3-chloro-5-((S)-4-chloro-2'-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6'-methyl-2,3,5',8'-tetrahydro-6'H- spiro[indene-1,7'-pyrido[4,3-d]pyrimidin]-4'-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (55) [00741] To a solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (76.63 mg, 0.48 mmol) in THF (1 mL) was added NaH (16.05 mg, 0.4 m
  • Step 2 To a solution of ethyl 3-chloro-5-[(7S)-4'-chloro-2-methylsulfanyl-spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxylate (57a) (65.mg, 0.12mmol) in DCM (1mL) was added diisobutylaluminium hydride (0.23mL, 0.23mmol) at -78 °C.
  • Step 4 To a solution of 1-[3-chloro-5-[(7S)-4'-chloro-2-methylsulfanyl-spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]-N,N-dimethyl-methanamine (57c) (40.mg, 0.07mmol) in THF (2mL) was added a solution of oxone (45.08mg, 0.15mmol) in Water (1mL) at 0 °C .
  • N-(3-chloropropyl)-2-nitro-N-prop-2- ynyl-benzenesulfonamide (Int-1b, 10g, 31.57mmol) and ethyl 2-diazoacetate (5403.14 mg, 47.35 mmol) in Chlorobenzene (80mL) was added N,N-Diisopropylethylamine (5.5 mL, 31.57 mmol) at 140 °C for 1.5 hours.
  • cesium carbonate (12.31 g, 37.88 mmol) was added and again heated to 140 °C for 30 minutes.
  • Step 1 Synthesis of 1,1-dimethoxy-4,4-bis(methylsulfanyl)but-3-en-2-one (Int-2a). To a solution of sodium hydride (6.77 g, 169.31 mmol) in THF (100 mL) was added Carbon Disulfide (5.1 mL, 84.65 mmol) at 0 °C. The mixture was stirred at 25 °C for 10 min. Then, a solution of 1,1-dimethoxypropan-2-one (10 g, 84.65 mmol) in THF (30 mL) was added at 0 °C. The mixture was stirred at 25 °C for 2 h.
  • Step 1 Synthesis of (NE,R)-2-methyl-N-tetralin-1-ylidene-propane-2-sulfinamide (64a).

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Abstract

Provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor and a compound of Formula (II).

Description

COMBINATION THERAPIES WITH KRAS MODULATORS CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Patent Application No.63/518,171 filed on August 8, 2023; the entire contents of which are incorporated herein by reference. BACKGROUND OF THE INVENTION [0002] The small GTPase protein Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) is a member of the Ras family of cell signaling switches, regulating growth and survival of normal and cancerous cells (e.g., see Cully, M. and J. Downward, SnapShot: Ras Signaling. Cell, 2008. 133(7): p.1292-1292 e1). KRAS mutations drive approximately 25% of human cancers by aberrant regulation of the mitogen-activated protein kinase (MAPK) signaling cascade and other effector pathways (e.g., see Stephen, A.G., et al., Dragging ras back in the ring. Cancer Cell, 2014.25(3): p.272-81). Though Ras has been recognized as a target in cancer for about 40 years, Ras-driven cancers remain among the most difficult to treat due to insensitivity to available targeted therapies. Ras, encoded by the three major genes KRAS, NRAS and HRAS, has the highest frequency of mutation of any oncogene. All oncogenic Ras mutations drive the switch to accumulate in the active GTP-bound state. The most common Ras mutation found across human tumor types is KRAS G12D (e.g., see The AACR Project GENIE Consortium. Cancer Discovery, 2017.7(8): p.818-831. Dataset Version 4). Activating mutations in codon 12 impair the small GTPases’ ability to perform their role in hydrolyzing GTP. This regulatory impairment is fundamental for initiating and maintaining tumor progression. [0003] Despite extensive efforts, small molecules have not been identified which block effector binding or restore GTPase activating protein (GAP) sensitivity, though some have been found which block interaction of Ras with the guanine nucleotide exchange factor (GEF), SOS, which activates Ras at the plasma membrane. KRAS G12C mutations, most common in lung adenocarcinoma, have been clinically shown to be susceptible to direct inhibition by covalent modification with small molecule inhibitors trapping the protein in the inactive GDP-bound state. KRAS G12D mutation confers a significantly slower intrinsic rate of GTP hydrolysis than G12C, resulting in more constitutive activation. Thus, pharmacological targeting the of inactive state is unlikely to achieve similar results against G12D, despite the existence of a similar binding pocket in the GDP-state. Additionally, a cysteine present at the site of the activating mutation yields itself to covalent chemistry, while aspartic acid does not provide typical medicinal chemistry approaches for selective covalent modification. [0004] In order to potentially exploit the accumulation of KRAS G12D and other mutant variants in the GTP-bound state as a vulnerability to achieve selective inhibition of cancer cells while sparing normal Ras function, it is attractive for small molecule inhibitors to bind to the GTP-state and stabilize a conformation that is incompetent for oncogenic signaling interactions with effector proteins. Furthermore, it has been shown that only constitutive activation of Raf, MEK and ERK kinases in the MAPK cascade downstream of Ras can bypass the requirement for Ras proteins in proliferative signaling (e.g., see Drosten, M., et al., Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival. EMBO J, 2010. 29(6): p. 1091-104). As all evidence has indicated that MAPK signaling is essential for the growth effects of Ras in cancer, KRAS- mutant-selective inhibition in this pathway is considered the critical functional readout for potential clinical benefit of novel therapeutic approaches. SUMMARY OF THE INVENTION [0005] In some embodiments, oncogenic KRas mutations create an immunosuppressive microenvironment which can result in resistance to immune checkpoint blockade (ICB) therapy, including anti-PD-1 and anti-PD-L1 inhibitors. Activated KRas has been demonstrated to repress the expression of interferon regulatory factor 2 (IRF2), which directly represses CXCL3 expression. This KRas-mediated repression of IRF2 leads to increased expression of CXCL3, which binds to CXCR2 on myeloid-derived suppressor cells (MDSC) promoting migration of these cells to the tumor microenvironment. In some cases, a role for KRas in modulating the immune microenvironment and primary ICB resistance in advanced colorectal cancer has been established. In colorectal cancer, anti-PD-1 resistance of KRAS-expressing tumors can be overcome by enforced IRF2 expression or by inhibition of CXCR2. (e.g., see Liao et al., (2019) Cancer Cell 35:559 - 572). In addition, oncogenic KRas signaling has been shown to promote tumor immunoresistance to ICB therapy by stabilizing PD-L1 mRNA via repression of the AU- rich element-binding protein tristetraprolin (TTP), which negatively regulates PD-L1 expression through AU-rich elements in the 3' UTR of PD-L1 mRNA (e.g., see Coelho et al., (2017) Immunity 47(6): 1083-1099). In some cases, oncogenic KRas has also been demonstrated to impair antigen presentation by repressing MHC I expression thereby allowing tumor cells to evade cytotoxic T-lymphocytes (e.g., see El-Jawhari et al., (2014) Molecular Immunology 58(2): 160-168), and KRas activating mutations upregulate IL-8 expression in NSCLC, and IL-8 plays a role in cell growth and migration in KRas-associated NSCLC (e.g., see Sunaga et al., (2012) Int. J. Cancer 130(8):1733-1744). [0006] Thus, activated KRas mutations or other KRas-activating generic alterations expression may modulate many aspects of the immune system and can be responsible for the immunosuppressive tumor microenvironment in KRas mutant or hyperactivated Kras wildtype- associated tumors. As such, the direct inhibition of KRas mutant or hyperactivated Kras wildtype-associated-mediated cell activity may reverse this reported immunosuppressive tumor microenvironment thereby improving the clinical activity of immune checkpoint blockade therapy, including the PD-1/PD-L1 pathway. [0007] As so, there is a need to develop combination therapies using KRas mutant or Kras wildtype inhibitors and ICB therapy, including anti-PD-1 and anti-PD-L1 inhibitors, for treating KRas mutant or hyperactivated Kras wildtype-associated cancers that can be resistant to ICB therapy. [0008] Additionally, beyond the compounds described herein direct potency against tumor cells, compounds described herein may modulate the tumor microenvironment (TME) in favor of antitumor immunity, by modulating tumor cell cytokine/chemokine release. [0009] Additionally, beyond the compounds described herein direct potency against tumor cells, compounds described herein may reprogram the tumor microenvironment (TME) in favor of antitumor immunity, by modulating tumor cell cytokine/chemokine release. Specifically, treatment with compounds described herein reduces immunosuppressive cytokine release while increasing immunostimulatory chemokine release in KRAS mutant cells. Results of our study herein (e.g., example 36) reveal a direct mechanism by which compounds described herein can modify tumor-cell-intrinsic immune signals to enhance antitumor immunity in a synergistic manner with the use of common immune checkpoint inhibitors. Our preclinical data provides strong rationale for clinical studies combining compounds described herein (e.g., compounds of Formula (II)) with, and expanding the therapeutic use of, existing checkpoint inhibitors (inhibitors targeting: cytotoxic T lymphocyte associated antigen 4 (CTLA-4), e.g. Yervoy/lpilimumab; programmed death 1/programmed death-ligand 1 (PD-1/PD-L1), e.g. Keytruda/pembrolizumab; and lymphocyte-activation gene 3 (LAG-3), e.g. BMS- 986016/relatlimab) for various types of cancers harboring oncogenic KRAS. [0010] In an aspect, the present disclosure provides combination therapies useful for treating a disease or disorder (e.g., cancer). In some cases, provided are therapeutically effective combinations of an agent that disrupts Programmed cell death protein 1 (PD-1) and Programmed death-ligand 1 (PD-L1) axis signaling (e.g., a PD-1 inhibitor, a PD-L1 inhibitor) and a compound of Formula (II), kits comprising the compositions and methods of use therefor. [0011] In an aspect, the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor and a compound represented by the structure of Formula (I):
Figure imgf000005_0001
Formula (I) or a pharmaceutically acceptable salt thereof wherein: R1 is selected from C3-C12 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; Y is selected from a bond, O, S and NR5; R2 is selected from hydrogen, -N(R21)2, -L-N(R21)2, -L-OR21, heterocycle, C1-C6 alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R21)2, -L-C1-C6 haloalkyl, -L-OR21, -L-NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L- N(R21)C(O)(OR21), -L-OC(O)N(R21)2, and -LC(=O)OC1-C6 alkyl, wherein the heterocycle and the aryl portion of -L-NR5C(O)-aryl and the heterocycle portion of -L-heterocycle and the cycloalkyl portion of the -L-cycloalkyl are optionally substituted with one or more R6, and wherein the aryl or heteroaryl of the -L-aryl and the -L-heteroaryl are optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; each R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, - OH, -CN, -NO2, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-10 alkyl, - C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R5 is independently selected from hydrogen or C1-C6 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1- C3 alkyl)C(=O), oxo, ( C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each R7 is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R5)2; each R20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, =NH, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R21 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each Q is independently selected from a bond, S, and O; B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, C1-6 alkyl-N(R20)2, C3-C12 carbocycle and 5- to 12- membered heterocycle, wherein C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and wherein B forms a spirocycle with Ring A; and Ring A is selected from a heterocycle and carbocycle, wherein the heterocycle or carbocycle is optionally substituted with one or more substituents selected from R4. [0012] In an aspect, the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a combination of an immunomodulator inhibitor and a compound represented by the structure of Formula (II):
Figure imgf000007_0001
Formula (II) or a pharmaceutically acceptable salt thereof wherein: M is selected from O, S, SO, SO2, and NR3; R1 is selected from C3-C12 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl-SO2R20, C1- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; Y is selected from a bond, O, S and NR5; R2 is selected from -L-N(R21)2, -L-OR21, heterocycle, C1-C6 alkyl, -L-heterocycle, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R21)2, -L-C1-C6 haloalkyl, -L- NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L- OC(O)N(R21)2, and -LC(=O)OC1-C6 alkyl, wherein the heterocycle, the aryl portion of -L- NR21C(O)-aryl, the heterocycle portion of -L-heterocycle, the cycloalkyl portion of the -L- cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of the -L- aryl and the heteroaryl portion of the -L-heteroaryl are each optionally substituted with one or more R7, and wherein when Y is a bond, O, or S, R2 is further selected from hydrogen; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkoxyalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; n is selected from 0 to 2; each R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, hydroxyl, halogen, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; each R5 is independently selected from hydrogen or C1-C6 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; each R7 is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R5)2; each R20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, =NH, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R21 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; and B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, C1-6 alkyl-N(R20)2, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. [0013] In an aspect, the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor and a compound represented by the structure of Formula (II):
Figure imgf000010_0001
Formula (II) or a pharmaceutically acceptable salt thereof wherein: M is selected from O, S, SO, SO2, and NR3; R1 is selected from C3-C12 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl-SO2R20, C1- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; Y is selected from a bond, O, S and NR5; R2 is selected from -L-N(R21)2, -L-OR21, heterocycle, C1-C6 alkyl, -L-heterocycle, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R21)2, -L-C1-C6 haloalkyl, -L- NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L- OC(O)N(R21)2, and -LC(=O)OC1-C6 alkyl, wherein the heterocycle, the aryl portion of -L- NR21C(O)-aryl, the heterocycle portion of -L-heterocycle, the cycloalkyl portion of the -L- cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of the -L- aryl and the heteroaryl portion of the -L-heteroaryl are each optionally substituted with one or more R7, and wherein when Y is a bond, O, or S, R2 is further selected from hydrogen; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkoxyalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; n is selected from 0 to 2; each R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, hydroxyl, halogen, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; each R5 is independently selected from hydrogen or C1-C6 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; each R7 is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R5)2; each R20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, =NH, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R21 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; and B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, C1-6 alkyl-N(R20)2, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. [0014] In some embodiments, for a compound or salt of Formula (II), when M is NR3, Y is O, and R1 is piperazine, the piperazine is substituted with one or more R9. In some cases, R1 is not piperazine. [0015] In an aspect, the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor and a compound represented by the structure of Formula (III):
Figure imgf000013_0001
Formula (III) or a pharmaceutically acceptable salt thereof wherein: R1 is selected from C3-C12 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; R2 is selected from -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L- OC(O)N(R21)2, and L-bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R6; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; n is selected from 0 to 3; each R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, hydroxyl, halogen, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; B is selected from a heterocycle and carbocycle, wherein the heterocycle or carbocycle is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2- C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, C1-6 alkyl-N(R20)2, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; Y is selected from a bond, O, S and NR5; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1- C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; each R20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R21 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; and each R5 is independently selected from hydrogen or C1-C6 alkyl. INCORPORATION BY REFERENCE [0016] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS [0017] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “figure” and “FIG.” herein), of which: [0018] FIG.1 illustrates that compounds herein reduce immunosuppressive cytokine release while increasing immunostimulatory chemokine release in KRAS-mutant HPAC cells. DETAILED DESCRIPTION OF THE INVENTION [0019] The following description sets forth numerous exemplary configurations, methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments. [0020] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the disclosure. However, one skilled in the art will understand that the disclosure may be practiced without these details. Definitions [0021] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference. [0022] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to fifteen carbon atoms (i.e., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (i.e., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5 alkyl). In certain embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. [0023] The term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “C1-6alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term –Cx-yalkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example –C1-6alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted. [0024] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above. [0025] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C2-C4 alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. [0026] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4 alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. [0027] The terms “Cx-yalkenyl” and “Cx-yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term –Cx-yalkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, –C2-6alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term –Cx-yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkenylene chain. For example, –C2-6alkenylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain. [0028] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain. In certain embodiments, an alkylene comprises one to ten carbon atoms (i.e., C1-C8 alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C1-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., C1 alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., C5-C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C3-C5 alkylene). [0029] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain. In certain embodiments, an alkenylene comprises two to ten carbon atoms (i.e., C2-C10 alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atom (i.e., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-C5 alkenylene). [0030] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain. In certain embodiments, an alkynylene comprises two to ten carbon atoms (i.e., C2-C10 alkynylene). In certain embodiments, an alkynylene comprises two to eight carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C5-C8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C3-C5 alkynylene). [0031] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. [0032] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like. [0033] "Aralkenyl" refers to a radical of the formula –Rd-aryl where Rd is an alkenylene chain as defined above. "Aralkynyl" refers to a radical of the formula -Re-aryl, where Re is an alkynylene chain as defined above. [0034] “Carbocycle” refers to a saturated, unsaturated or aromatic rings in which each atom of the ring is carbon. Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Bicyclic carbocycles may be fused, bridged or spiro-ring systems. In some cases, spiro-ring carbocycles have at least two molecular rings with only one common atom. [0035] The term “unsaturated carbocycle” refers to carbocycles with at least one degree of unsaturation and excluding aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene. [0036] "Cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. [0037] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond. In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms. In other embodiments, a cycloalkenyl comprises five to seven carbon atoms. The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. [0038] "Cycloalkylalkyl" refers to a radical of the formula –Rc-cycloalkyl where Rc is an alkylene chain as described above. [0039] "Cycloalkylalkoxy" refers to a radical bonded through an oxygen atom of the formula – O-Rc-cycloalkyl where Rc is an alkylene chain as described above. [0040] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents. [0041] As used herein, the term "haloalkyl" or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2- haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected e.g., 1-chloro,2-fluoroethane. [0042] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. [0043] "Aminoalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more amine radicals, for example, propan-2-amine, butane-1,2-diamine, pentane-1,2,4-triamine and the like. [0044] "Hydroxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, for example, propan-1-ol, butane-1,4-diol, pentane-1,2,4-triol, and the like. [0045] "Alkoxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more alkoxy radicals, for example, methoxymethane, 1,3-dimethoxybutane, 1-methoxypropane, 2-ethoxypentane, and the like. [0046] "Cyanoalkyl" as used herein refers to an alkyl radical, as defined above, that is substituted by one or more cyano radicals, for example, acetonitrile, 2-ethyl-3- methylsuccinonitrile, butyronitrile, and the like. [0047] “Heterocycle” as used herein refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. A bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. In an exemplary embodiment, an aromatic ring, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. A bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5- 6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Bicyclic heterocycles may be fused, bridged, or spiro-ring systems. A spiro-ring system may be referred as a “spiroheterocycle”, “spiro heterocycle”, or “spiro-heterocycle”. In some cases, spiro-heterocycles, spiro heterocycles, or spiroheterocycles have at least two molecular rings with only one common atom. The spiro- heterocycle, spiro heterocycle, or spiroheterocycle comprises one or more heteroatoms. [0048] “Heterocyclene” refers to a divalent heterocycle linking the rest of the molecule to a radical group. [0049] "Heteroaryl" or “aromatic heterocycle” refers to a radical derived from a heteroaromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ^– electron system in accordance with the Hückel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryls include, but are not limited to, pyridine, pyrimidine, oxazole, furan, pyran, thiophene, isoxazole, benzimidazole, benzthiazole, and imidazopyridine. [0050] An “X-membered heteroaryl” refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc. [0051] The term “unsaturated heterocycle” refers to heterocycles with at least one degree of unsaturation and excluding aromatic heterocycles. Examples of unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine. Heterocycles may be optionally substituted by one or more substituents such as those substituents described herein. [0052] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. [0053] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -R b-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocycle, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -R b-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); wherein each Ra is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -R b-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and wherein each Rb is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rc is a straight or branched alkylene, alkenylene or alkynylene chain. [0054] As used herein, the term “electrophile” or “electrophilic moiety” is any moiety capable of reacting with a nucleophile (e.g., a moiety having a lone pair of electrons, a negative charge, a partial negative charge and/or an excess of electrons, for example an —SH group). Electrophiles typically are electron poor or comprise atoms which are electron poor. In certain embodiments, an electrophile contains a positive charge or partial positive charge, has a resonance structure which contains a positive charge or partial positive charge, or is a moiety in which delocalization or polarization of electrons results in one or more atoms which contains a positive charge or partial positive charge. In some embodiments, an electrophile comprises a conjugated double bond, for example an α,β-unsaturated carbonyl or α,β-unsaturated thiocarbonyl compound. [0055] As used herein, the term “optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution. [0056] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise. [0057] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. [0058] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. [0059] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0060] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. [0061] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample. [0062] The terms “treat,” “treating” or “treatment,” as used herein, may include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically. [0063] The term “G12 mutants”, as used herein, refers to other oncogenic alleles of KRAS at amino acid position 12 (ie. G12X). [0064] The term "KRas G12D-associated cancer" as used herein refers to cancers associated with or mediated by or having a KRas G12D mutation. [0065] The term "KRas G12V-associated cancer" as used herein refers to cancers associated with or mediated by or having a KRas G12V mutation. [0066] The term "KRas wildtype-associated cancer" as used herein refers to cancers associated with or mediated by or having a KRas wildtype. [0067] The term “immunomodulator inhibitor” refers to an agent that modifies, or modulates, the immune system to help a subject respond to a disease or disorder. [0068] The term “PD-1 inhibitor” refers to an agent that is capable of negatively modulating or inhibiting all or a portion of the PD-1 axis signaling activity and include agents that block PD-1. [0069] The term “PD-L1 inhibitor” refers to an agent that is capable of negatively modulating or inhibiting all or a portion of the PD-L1 axis signaling activity and include agents that block PD-L1. [0070] The term “PD-1 binding antagonist” is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and/or PD-L2. [0071] The term “PD-L1 binding antagonist” is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-1 and/or B7-1. [0072] The term “biosimilar” means an antibody or antigen-binding fragment that has the same primary amino acid sequence as compared to a reference antibody (e.g., nivolumab or pembrolizumab) and optionally, may have detectable differences in post-translation modifications (e.g., glycosylation and/or phosphorylation) as compared to the reference antibody (e.g., a different glycoform). [0073] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans, as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker. [0074] As used herein, the phrase "a subject in need thereof" refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein. [0075] The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of” can include determining the amount of something present in addition to determining whether it is present or absent depending on the context. [0076] The terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, oral routes of administering a composition can be used. The terms “administer”, “administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the disclosure or a prodrug of a compound of the disclosure to the individual in need. [0077] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or salt described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term can also apply to a dose that can induce a particular response in target cells, e.g., reduction of proliferation or down regulation of activity of a target protein. The specific dose can vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried. [0078] As used herein, a "therapeutically effective amount of a combination" of two compounds is an amount that together synergistically increases the activity of the combination in comparison to the therapeutically effective amount of each compound in the combination, i.e., more than merely additive. [0079] As used herein, “synergy,” “synergetic,” “synergism,” or “synergistic effect” refer to two or more compounds or compositions, that individually produce an effect, however, together produce a combined effect that is greater than their individual effects. [0080] The term “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value. [0081] It is intended that every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this specification will include every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein. [0082] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. [0083] Any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein. COMPOSITIONS AND INHIBITORS Immunomodulator Inhibitors [0084] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a combination of: i) an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. [0085] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. [0086] In some embodiments, Formula (II) is represented by Formula (II*). [0087] In some embodiments, the immunomodulator inhibitor is selected from a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor. In some cases, the immunomodulator inhibitor is a PD-1 inhibitor. In some cases, the immunomodulator inhibitor is a PD-L1 inhibitor. In some cases, the immunomodulator inhibitor is a CTLA-4 inhibitor. [0088] In some embodiments, the immunomodulator inhibitor is selected from a PD-1/PD-L1 checkpoint inhibitor. [0089] In some embodiments, the immunomodulator inhibitor is immune checkpoint inhibitor. [0090] In some embodiments, the immunomodulator inhibitor is pembrolizumab. [0091] In some embodiments, the immunomodulator inhibitor is relatlimab. PD-1/PD-L1 Inhibitors [0092] In some embodiments, programmed death protein 1 (PD-1) is an immunoinhibitory receptor that is primarily expressed on activated T and B cells. PD-1 is a 55 kDa type I transmembrane protein that is part of the Ig gene superfamily (Agata et al. (1996) Int Immunol 8:765-72). PD-1 contains a membrane proximal immunoreceptor tyrosine inhibitory motif (ITIM) and a membrane distal tyrosine-based switch motif (ITSM). Two ligands that bind to PD-1 have been identified, PD-L1 and PD-L2, that have been shown to downregulate T cell activation upon binding to PD-1 (Freeman et al. (2000) J Exp Med 192: 1027-34). PD-L1 is a ligand for PD-1 and is abundant in a variety of human cancers (Dong et al. (2002) Nat. Med.8:787-9). In some cases, the interaction between PD-1 and PD-L1 results in a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and immune evasion by the cancerous cells (Dong et al. (2003) J. Mol. Med.81:281-7). [0093] In some embodiments, immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-Ll, and the effect is additive when the interaction of PD-1 with PD- L2 is blocked as well. In some cases, disruption of the PD-1/PD-L1 interaction has been shown to increase T cell proliferation and cytokine production and block progression of the cell cycle. [0094] In some embodiments, PD-L1 is upregulated in many cancers and contributes to evasion of the host immune system, blocking the interaction between PD-1 and PD-L1 has garnered the attention of the pharmaceutical industry leading to a new break-through class of immune checkpoint therapies for a wide range of cancers. In some cases, the PD-1/PD-L1 pathway is a well-validated target for the development of antibody therapeutics for cancer treatment and several anti-PD-1 and anti-PD-L1 antibodies have undergone human clinical trials for a wide-variety of cancers including NSCLC, renal cell carcinoma, melanoma, head and neck squamous cancer, ureothelial cancer, hepatocellular carcinoma, and other cancers. In some cases, anti-PD-1 antibodies include nivolumab (Opdivo®), pembrolizumab (Keytruda®), cemiplimab (Libtayo®) and tislelizumab, and biosimilars thereof. In some cases, anti-PD-L1 antibodies include atezolizumab (Tecentriq®), avelumab (Bavencio®), and durvalumab (Imfinzi®), and biosimilars thereof. [0095] In some embodiments, methods for manufacturing agents that disrupt PD-1/PD-L1 signaling axis, including the antibodies described herein, are well known to those skilled in the art and agents that disrupt PD-1/PD-L1 signaling axis may be obtained from a wide-variety of commercial suppliers, in forms suitable for both research or approved human clinical use. In some cases, suitable agents that disrupt PD-1/PD-L1 signaling for use in the compositions and methods disclosed herein and methods for preparing such agents, and diagnostic and efficacy markers useful for monitoring treatment are disclosed in US Patent Application Publication Nos: 20180327848; 20180237524; 20180148790; 20180111996; 20160305947; 20160304969; 20160304606; 20150232555; 20150079109; 20140348743; 20140294852; 20140271684; 20140234296; 20130133091; 20110123550; and 20090217401. PD-1 inhibitor [0096] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a combination of: i) an PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. [0097] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) an PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. [0098] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) an PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. [0099] In some embodiments, Formula (II) is represented by Formula (II*). [00100] In some embodiments, a PD-1 inhibitor is selected from a PD-1 binding antagonist. In some cases, the PD-1 binding antagonist is selected from anti-PD-1 antibodies, antigen binding fragments thereof, immunoadhesins, aptamers, fusion proteins, and oligopeptides. In some cases, the PD-1 binding antagonist is an anti-PD-1 antibody. [00101] In some embodiments, the PD-1 inhibitor is a molecule that inhibits the binding of PD-1 to its binding partners. In some cases, the PD-1 inhibitor inhibits the binding of PD-1 to PD-L1 and/or PD-L2. In some cases, PD-1 inhibitors include anti-PD-1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and/or PD-L2. In some cases, a PD-1 inhibitor reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T-cell less non- dysfunctional. In some cases, the PD-1 inhibitor is an anti-PD-1 antibody. In some cases, the PD- 1 antibody is pembrolizumab, or a biosimilar thereof. In some cases, the PD-1 antibody is cemiplimab, or a biosimilar thereof. In some cases, the PD-1 antibody is tislelizumab, or a biosimilar thereof. PD-L1 Inhibitors [00102] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a combination of: i) an PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. [00103] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) an PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. [00104] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) an PD-L1 inhibitor, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof. [00105] In some embodiments, Formula (II) is represented by Formula (II*). [00106] In some embodiments, a PD-L1 inhibitor is selected from a PD-L1 binding antagonist. In some cases, the PD-L1 binding antagonist is selected from an anti-PD-L1 antibody, antigen binding fragments thereof, immunoadhesins, aptamers, fusion proteins, and oligopeptides. In some cases, the PD-L1 binding antagonist is an anti-PD-L1 antibody. [00107] In some embodiments, a PD-L1 inhibitor is a molecule that inhibits the binding of PD- L1 to its binding partners. In some cases, the PD-L1 inhibitor inhibits binding of PD-L1 to PD-1 and/or B7-1. In some cases, the PD-L1 inhibitors include anti-PD-L1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and/or B7-1. In some cases, a PD-L1 inhibitor reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L1 so as render a dysfunctional T-cell less non-dysfunctional. In some cases, a PD-L1 inhibitor is an anti-PD-L1 antibody. In some cases, an anti- PD-L1 antibody is avelumab or a biosimilar thereof. In some cases, an anti-PD-L1 antibody is atezolizumab or a biosimilar thereof. In some cases, an anti-PD- L1 antibody is durvalumab or a biosimilar thereof. In some cases, an anti-PD-L1 antibody is BMS-936559 (MDX-1105) or a biosimilar thereof. CTLA-4 inhibitor [00108] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a combination of: i) an CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. [00109] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) an CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. [00110] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) an CTLA-4 inhibitor, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof. [00111] In some embodiments, Formula (II) is represented by Formula (II*). [00112] In some embodiments, the CTLA-4 inhibitor is selected from lpilimumab. KRAS Inhibitors [00113] The following is a discussion of compounds and salts thereof that may be used in the methods of the disclosure. The compounds and salts (e.g., a compound of Formula (I), Formula (II), Formula (II*), or Formula (III)) may be used in combination with at least one other inhibitor (e.g., immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor). The compounds and salts (e.g., a compound of Formula (I), Formula (II), Formula (II*), or Formula (III)) may be used in combination with one other inhibitor (e.g., immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor). In some cases, a compound of Formula (I), Formula (II), Formula (III), or sub Formulas thereof, may be used in the methods of the disclosure. In some cases, a compound of Formula (I), Formula (II), Formula (III), or sub Formulas thereof, may be referred to as a KRAS inhibitor. In some cases, a compound of Formula (I), Formula (II), Formula (III), or Formula (II*), may be referred to as a KRAS inhibitor. [00114] In some embodiments, a compound represented by the structure of Formula (I):
Figure imgf000033_0001
or a pharmaceutically acceptable salt thereof wherein: R1 is selected from C3-C12 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; Y is selected from a bond, O, S and NR5; R2 is selected from hydrogen, -N(R21)2, -L-N(R21)2, -L-OR21, heterocycle, C1-C6 alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R21)2, -L-NHC(=NH)NH2, -L- C(O)N(R21)2, -L-C1-C6 haloalkyl, -L-OR21, -L-NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L- S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L-OC(O)N(R21)2, or -LC(=O)OC1-C6 alkyl, wherein the heterocycle and the aryl portion of -L-NR5C(O)-aryl and the heterocycle portion of -L-heterocycle and the cycloalkyl portion of the -L-cycloalkyl are optionally substituted with one or more R6, and wherein the aryl or heteroaryl of the -L-aryl and the -L-heteroaryl are optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; each R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, - OH, -CN, -NO2, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R5 is independently selected from hydrogen and C1-C6 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1- C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each R7 is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R5)2; each R20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, =NH, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R21 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each Q is independently selected from a bond, S, and O; B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, C1-6 alkyl-N(R20)2, C3-C12 carbocycle and 5- to 12- membered heterocycle, wherein C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and wherein B forms a spirocycle with Ring A; and Ring A is selected from a heterocycle and carbocycle, wherein the heterocycle or carbocycle is optionally substituted with one or more substituents selected from R4. [00115] In some embodiments, Formula (I) is represented by Formula (II), Formula (II*), or Formula (III). [00116] In some embodiments, for a compound or salt of Formula (I), Ring A is selected from a heterocycle wherein the heterocycle is optionally substituted with one or more substituents selected from R4. In some cases, Ring A includes at least one heteroatom selected from nitrogen, sulfur, and oxygen. In some cases, the heteroatom of Ring A is nitrogen, wherein the nitrogen is optionally substituted with R3, wherein R3 is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, the heteroatom of Ring A is sulfur, wherein the sulfur is optionally substituted with 1 or 2 oxygen atoms. In some cases, the heteroatom of Ring A is oxygen. [00117] In some embodiments, for a compound or salt of Formula (I), Ring A is selected from a carbocycle, wherein the carbocycle is optionally substituted with one or more substituents selected from R4. [00118] In some embodiments, for a compound or salt of Formula (I), R2 is selected from -L- NR21S(O)2(R21) and -L-S(O)2N(R21)2. [00119] In some embodiments, for a compound or salt of Formula (I), R2 is selected from -L- N(R21)C(O)(OR21), and -L-OC(O)N(R21)2. [00120] In some embodiments, for a compound or salt of Formula (I), each R21 is independently selected from hydrogen; C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, and oxo. In some cases, each R21 is independently selected from hydrogen; C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R21 is independently selected from hydrogen and C1-6 alkyl. [00121] In some embodiments, for a compound or salt of Formula (I), R2 is selected from L- bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R6. [00122] In some embodiments, for a compound or salt of Formula (I), R2 is selected from L- pyrrolizine, wherein the pyrrolizine is optionally substituted with one or more R6. [00123] In some embodiments, for a compound or salt of Formula (I), each L is independently selected from an optionally substituted C1-C4 alkylene; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, - NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6 haloalkyl. [00124] In some embodiments, for a compound or salt of Formula (I), each L is independently selected from a substituted C1-C4 alkylene, wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. [00125] In some embodiments, for a compound or salt of Formula (I), wherein each L is independently selected from a substituted C1-C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, each L is independently selected from a substituted C3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle. In some cases, each L is independently selected from
Figure imgf000037_0001
. [00126] In some embodiments, for a compound or salt of Formula (I), R2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. In some cases, the heterocycle is a saturated heterocycle. In some cases, the heterocycle has at least one nitrogen atom and at least one sulfur atom. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom. [00127] In some embodiments, for a compound or salt of Formula (I), R2 is selected from
Figure imgf000038_0001
, wherein the heterocycle portion is optionally substituted with one or more R6. [00128] In some embodiments, for a compound or salt of Formula (I), Y-R2 is selected from
Figure imgf000038_0002
, wherein the heterocycle portion is optionally substituted with one or more R6. [00129] In some embodiments, for a compound or salt of Formula (I), Y-R2 is selected from
Figure imgf000038_0003
, wherein the heterocycle portion is optionally substituted with one or more R6. [00130] In some embodiments, for a compound or salt of Formula (I), Y-R2 is selected from
Figure imgf000038_0004
and
Figure imgf000038_0005
, wherein the heterocycle portion is optionally substituted with one or more R6. [00131] In some embodiments, for a compound or salt of Formula (I), R2 is selected from -L- saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R6, and contains one nitrogen atom and one sulfur atom.
Figure imgf000038_0006
the heterocycle portion is optionally substituted with one or more R6. In some cases, Y-R2 is selected from
Figure imgf000038_0007
, wherein the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3 alkyl and oxo. In some cases, Y-R2 is selected from
Figure imgf000039_0001
cases, Y-R2 is selected from
Figure imgf000039_0002
[00132] In some embodiments, for a compound or salt of Formula (I), each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1- C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo. [00133] In some embodiments, for a compound or salt of Formula (I), each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. [00134] In some embodiments, for a compound or salt of Formula (I), each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R5)2, and oxo. In some cases, each R6 is independently selected from -OH, Cl- C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, each R6 is independently selected from C1-C3 alkyl, C1-C3 alkoxy, and -N(R5)2. [00135] In some embodiments, for a compound or salt of Formula (I), R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. In some cases, R6 is selected from halogen and C1-C3 alkyl. In some cases, R6 is halogen. In some cases, R6 is C1-C3 alkyl. In some cases, R6 is selected from halogen and C1-C3 alkyl. In some cases, R6 is selected from methyl and fluorine. [00136] In some embodiments, for a compound or salt of Formula (I), R2 is selected from
Figure imgf000039_0003
[00137] In some embodiments, for a compound or salt of Formula (I), Y-R2 is selected from
Figure imgf000040_0001
[00138] In some embodiments, for a compound or salt of Formula (I), Y-R2 is selected from
Figure imgf000040_0002
[00139] In some embodiments, for a compound or salt of Formula (I), Y-R2 is
Figure imgf000040_0003
. [00140] In some embodiments, for a compound or salt of Formula (I), Y-R2 is selected from , and
Figure imgf000040_0004
. [00141] In some embodiments, for a compound or salt of Formula (I), B is an optionally substituted 5- to 15-membered heterocycle or optionally substituted C3-C15 carbocycle. In some cases, B is an optionally substituted 5- to 15-membered heterocycle. In some cases, B is an optionally substituted C3-C15 carbocycle. [00142] In some embodiments, for a compound or salt of Formula (I), B is an optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted C8-C15 fused carbocycle. [00143] In some embodiments, for a compound or salt of Formula (I), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15- membered fused heterocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle are each bicyclic or tricyclic. [00144] In some embodiments, for a compound or salt of Formula (I), B the heterocycle or carbocycle are each independently bicyclic. In some cases, the heterocycle is bicyclic. In some cases, the carbocycle is bicyclic. [00145] In some embodiments, for a compound or salt of Formula (I), B the heterocycle or carbocycle are each independently tricyclic. In some cases, the heterocycle is tricyclic. In some cases, the carbocycle is tricyclic. [00146] In some embodiments, for a compound or salt of Formula (I), B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from
Figure imgf000041_0001
Figure imgf000041_0002
, each of which is optionally substituted with one or more substituents. [00147] In some embodiments, for a compound or salt of Formula (I), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from , , , , , and , each of which is optionally substituted with one or more substituents. [00148] In some embodiments, for a compound or salt of Formula (I), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from, , and , each of which is optionally substituted with one or more substituents. [00149] In some embodiments, for a compound or salt of Formula (I), for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, C1-C3 alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, - NHCN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3 alkyl, -B(OR20)2, -OH, -C(O)N(R20)2, =O, -CN, C1-6 alkoxy, and C2-6 alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, -OH, -C(O)NH2, -NH2, =O, - CN, C1-6 alkoxy, and C2-6 alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from oxo, -NH2, -CN, halogen, C1-C3 alkyl. In some cases, the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH2, halogen, C1-C3 alkyl. [00150] In some embodiments, for a compound or salt of Formula (I), B is selected from ,
Figure imgf000042_0001
[00151] In some embodiments, for a compound or salt of Formula (I), for B, the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH2, CN, halogen, C1-C3 alkyl. [00152] In some embodiments, for a compound or salt of Formula (I), B is selected from
Figure imgf000043_0001
[00153] In some embodiments, for a compound or salt of Formula (I), each R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, hydroxyl, halogen. Ins some cases, each R4 is independently selected from C1-6 alkyl, oxo, and halogen. [00154] In some embodiments, for a compound or salt of Formula (I), n is selected from 1 and 2. In some cases, n is 0. [00155] In some embodiments, for a compound or salt of Formula (I), Y is O. [00156] In some embodiments, for a compound or salt of Formula (I), R1 is selected from optionally substituted 5- to 12-membered heterocycle. [00157] In some embodiments, for a compound or salt of Formula (I), R1 is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, SR20, - S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20, -N(R20)2, -C(O)R20, C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =NO(R20), CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1- 6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. [00158] In some embodiments, for a compound or salt of Formula (I), R1 is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, - S(O)2(R20), -C(O)N(R20)2, -C(O)NR20-OR20, -S(O)2N(R20)2, -NR20S(O)2R20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, OC(O)N(R20)2, -NO2, =O, =NO(R20), -CN, -NHCN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl [00159] In some embodiments, for a compound or salt of Formula (I), R1 is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -N(R20)C(O)OR20, and -OC(O)N(R20)2. [00160] In some embodiments, for a compound or salt of Formula (I), R1 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. [00161] In some embodiments, for a compound or salt of Formula (I), R1 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. [00162] In some embodiments, for a compound or salt of Formula (I), R20 of R1 is selected from hydrogen and C1-3 alkyl. [00163] In some embodiments, for a compound or salt of Formula (I), the 5- to 12-membered heterocycle of R1 is an unsaturated heterocycle. [00164] In some embodiments, for a compound or salt of Formula (I), the 5- to 12-membered heterocycle of R1 is a saturated heterocycle. [00165] In some embodiments, for a compound or salt of Formula (I), 5- to 12-membered heterocycle of R1 is a bridged heterocycle. [00166] In some embodiments, for a compound or salt of Formula (I), R1 is selected from
Figure imgf000044_0001
Figure imgf000045_0001
, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, =O, -CN, C1-6 hydroxyalkyl, and C1-6 haloalkyl. [00167] In some embodiments, for a compound or salt of Formula (I), R1 is selected from
Figure imgf000045_0002
substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, - NO2, C1-6 aminoalkyl, C1-6 alkoxy, =O, -CN, C1-6 hydroxyalkyl, and C1-6 haloalkyl. [00168] In some embodiments, for a compound or salt of Formula (I), R1 is selected from
Figure imgf000045_0003
[00169] In some embodiments, for a compound or salt of Formula (I), L is selected from C1-C4 alkylene. [00170] In some embodiments, for a compound or salt of Formula (I), L is selected from unsubstituted C1-C4 alkylene. [00171] In some embodiments, for a compound or salt of Formula (I), R2 is -L-heterocycle, optionally substituted with one or more R6, wherein the heterocycle portion is a bicyclic heterocycle. In some cases, the bicyclic heterocycle contains at least 1 nitrogen atom. In some cases, the bicyclic heterocycle contains at most 1 nitrogen atom. [00172] In some embodiments, for a compound or salt of Formula (I), Y-R2 is selected from
Figure imgf000045_0004
, wherein the heterocycle portion is optionally substituted with one or more R6. [00173] In some embodiments, for a compound or salt of Formula (I), R6 of R2 is independently selected at each occurrence from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl. [00174] In some embodiments, for a compound or salt of Formula (I), R6 of R2 is independently selected at each occurrence from C1-C3 alkyl and halogen. [00175] In some embodiments, for a compound or salt of Formula (I), Y-R2 is selected from
Figure imgf000046_0001
[00176] In some embodiments, a compound is represented by the structure of Formula (II):
Figure imgf000046_0002
Formula (II) or a pharmaceutically acceptable salt thereof wherein: M is selected from O, S, SO, SO2, and NR3; R1 is selected from C3-C12 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl-SO2R20, C1- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; Y is selected from a bond, O, S and NR5; R2 is selected from -L-N(R21)2, -L-OR21, heterocycle, C1-C6 alkyl, -L-heterocycle, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R21)2, -L-C1-C6 haloalkyl, -L- OR21, -L-NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L- N(R21)C(O)(OR21), -L-OC(O)N(R21)2, and -LC(=O)OC1-C6 alkyl, wherein the heterocycle, the aryl portion of -L-NR21C(O)-aryl, the heterocycle portion of -L-heterocycle, the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of the -L- aryl and the heteroaryl portion of the -L-heteroaryl are each optionally substituted with one or more R7, and wherein when Y is a bond, O, or S, R2 is further selected from hydrogen; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkoxyalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; n is selected from 0 to 2; each R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, hydroxyl, halogen, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; each R5 is independently selected from hydrogen or C1-C6 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; each R7 is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R5)2; each R9 is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -NR20S(O)2R20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, - N(R20)2, -NO2, =O, =NO(R20), -CN, -NHCN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; each R20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, =NH, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R21 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; and B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, C1-6 alkyl-N(R20)2, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. [00177] In some embodiments, for a compound or salt of Formula (II), R2 is selected from -L- NR21S(O)2(R21) and -L-S(O)2N(R21)2. [00178] In some embodiments, for a compound or salt of Formula (II), R2 is selected from -L- N(R21)C(O)(OR21), and -L-OC(O)N(R21)2. [00179] In some embodiments, for a compound or salt of Formula (II), each R21 is independently selected from hydrogen; C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O- C1-10 alkyl, and oxo. In some cases, each R21 is independently selected from hydrogen; C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R21 is independently selected from hydrogen and C1-6 alkyl. [00180] In some embodiments, for a compound or salt of Formula (II), R3 is selected from hydrogen and C1-6 alkyl. [00181] In some embodiments, for a compound or salt of Formula (II), M is selected from O, NH, and NMe. In some cases, M is O. In some cases, M is selected from NH and NMe. [00182] In some embodiments, for a compound or salt of Formula (II), B is an optionally substituted 5- to 15-membered heterocycle or optionally substituted C3-C15 carbocycle. In some cases, B is an optionally substituted 5- to 15-membered heterocycle. In some cases, B is an optionally substituted C3-C15 carbocycle. In some cases, B is an optionally substituted 8- to 15- membered heterocycle. In some cases, B is an optionally substituted C8-C15 carbocycle. [00183] In some embodiments, for a compound or salt of Formula (II), B is an optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted C8-C15 fused carbocycle. [00184] In some embodiments, for a compound or salt of Formula (II), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15- membered fused heterocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle are each bicyclic or tricyclic. [00185] In some embodiments, for a compound or salt of Formula (II), for B, the optionally substituted 8- to 15-membered heterocycle contains at least one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least two heteroatoms. [00186] In some embodiments, for a compound or salt of Formula (II), B the heterocycle or carbocycle are each independently bicyclic. In some cases, the heterocycle is bicyclic. In some cases, the carbocycle is bicyclic. [00187] In some embodiments, for a compound or salt of Formula (II), B the heterocycle or carbocycle are each independently tricyclic. In some cases, the heterocycle is tricyclic. In some cases, the carbocycle is tricyclic. [00188] In some embodiments, for a compound or salt of Formula (II), B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from
Figure imgf000050_0001
Figure imgf000050_0002
, each of which is optionally substituted with one or more substituents. [00189] In some embodiments, for a compound or salt of Formula (II), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from
Figure imgf000050_0003
,
Figure imgf000050_0004
each of which is optionally substituted with one or more substituents. [00190] In some embodiments, for a compound or salt of Formula (II), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from,
Figure imgf000050_0005
, each of which is optionally substituted with one or more substituents. [00191] In some embodiments, for a compound or salt of Formula (II), for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, C1-C3 alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, - NHCN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3 alkyl, -B(OR20)2, -OH, -C(O)N(R20)2, =O, -CN, C1-6 alkoxy, and C2-6 alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, -OH, -C(O)NH2, -NH2, =O, - CN, C1-6 alkoxy, and C2-6 alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from oxo, -NH2, -CN, halogen, C1-C3 alkyl. In some cases, the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH2, halogen, C1-C3 alkyl. [00192] In some embodiments, for a compound or salt of Formula (II), B is selected from
Figure imgf000051_0001
Figure imgf000052_0001
[00193] In some embodiments, for a compound or salt of Formula (II), B is selected from
Figure imgf000052_0002
. [00194] In some embodiments, for a compound or salt of Formula (II), each R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, hydroxyl, halogen. Ins some cases, each R4 is independently selected from C1-6 alkyl, oxo, and halogen. [00195] In some embodiments, for a compound or salt of Formula (II), n is selected from 1 and 2. In some cases, n is 0. [00196] In some embodiments, for a compound or salt of Formula (II), Y is O. [00197] In some embodiments, for a compound or salt of Formula (II), R1 is selected from optionally substituted 5- to 12-membered heterocycle. [00198] In some embodiments, for a compound or salt of Formula (II), R1 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, - NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. [00199] In some embodiments, for a compound or salt of Formula (II), R1 is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, SR20, - S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20,-N(R20)2, -C(O)R20, C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =NO(R20), CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. [00200] In some embodiments, for a compound or salt of Formula (II), R1 is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -N(R20)C(O)OR20, and -OC(O)N(R20)2. [00201] In some embodiments, for a compound or salt of Formula (II), R1 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, - NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. [00202] In some embodiments, for a compound or salt of Formula (II), R20 of R1 is selected from hydrogen and C1-3 alkyl. [00203] In some embodiments, for a compound or salt of Formula (II), the 5- to 12-membered heterocycle of R1 is an unsaturated heterocycle. [00204] In some embodiments, for a compound or salt of Formula (II), the 5- to 12-membered heterocycle of R1 is a saturated heterocycle. [00205] In some embodiments, for a compound or salt of Formula (II), 5- to 12-membered heterocycle of R1 is a bridged heterocycle. [00206] In some embodiments, for a compound or salt of Formula (II), R1 is selected from
Figure imgf000053_0001
Figure imgf000054_0001
, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, =O, -CN, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some embodiments, for a compound or salt of Formula (II), R1 is selected from
Figure imgf000054_0002
,
Figure imgf000054_0003
one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, =O, -CN, C1-6 hydroxyalkyl, and C1-6 haloalkyl. [00207] In some embodiments, for a compound or salt of Formula (II), R1 is selected from
Figure imgf000054_0004
[00208] In some embodiments, for a compound or salt of Formula (II), R1 is selected from an optionally substituted saturated 6- to 7-membered heterocycle. In some cases, R1 is selected from an optionally substituted saturated 6-membered heterocycle. In some cases, R1 is selected from
Figure imgf000054_0005
, which is optionally substituted. In some cases, the optional one or more substituents are independently selected from halogen, -CN, -NHCN, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, the optional one or more substituents are independently selected from -NHCN, and C1-6 alkyl. In some cases, R1 is selected from
Figure imgf000054_0006
, which is substituted with one or more substituents selected from -NHCN, and C1-6 alkyl. In some cases, R1 is selected from
Figure imgf000055_0001
Figure imgf000055_0002
. [00209] In some embodiments, for a compound or salt of Formula (II), R1 is selected from a substituted saturated 6-membered heterocycle, wherein the saturated 6-membered heterocycle is substituted with at least one -NHCN, and optionally one or more C1-6 alkyl; M is O; n is 0; B is selected from an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15 fused carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, oxo, -NH2, C1-C3 alkyl, -OH, -C(O)NH2, - NH2, =O, -CN, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl; Y is O; R2 is selected from -L- heterocycle, wherein the heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R5)2; and L is selected from C1-C4 alkylene. In some cases,
Figure imgf000055_0003
, . [00210] In some embodiments, for a compound or salt of Formula (II), each R9 is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -NO2, =O, =NO(R20), -CN, - NHCN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, each R9 is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, - NR20S(O)2R20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -NO2, =O, =NO(R20), -CN, -NHCN. In some cases, each R9 is independently selected from halogen, -SR20, - S(O)2(R20), -S(O)2N(R20)2, -N(R20)2, -NO2, =O, and =NO(R20). In some cases, each R9 is independently selected from halogen, and -N(R20)2. [00211] In some embodiments, for a compound or salt of Formula (II), each L is independently selected from an optionally substituted C1-C4 alkylene; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, - NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6 haloalkyl. [00212] In some embodiments, for a compound or salt of Formula (II), each L is independently selected from a substituted C1-C4 alkylene, wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. [00213] In some embodiments, for a compound or salt of Formula (II), wherein each L is independently selected from a substituted C1-C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, each L is independently selected from a substituted C3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle. In some cases, each L is independently selected from
Figure imgf000056_0001
. [00214] In some embodiments, for a compound or salt of Formula (II), R2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. In some cases, the heterocycle is a saturated heterocycle. In some cases, the heterocycle has at least one nitrogen atom and at least one sulfur atom. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom. [00215] In some embodiments, for a compound or salt of Formula (II), R2 is selected from
Figure imgf000057_0001
, wherein the heterocycle portion is optionally substituted with one or more R6. [00216] In some embodiments, for a compound or salt of Formula (II), Y-R2 is selected from
Figure imgf000057_0002
, wherein the heterocycle portion is optionally substituted with one or more R6. [00217] In some embodiments, for a compound or salt of Formula (II), Y-R2 is selected from
Figure imgf000057_0003
, wherein the heterocycle portion is optionally substituted with one or more R6. [00218] In some embodiments, for a compound or salt of Formula (II), Y-R2 is selected from
Figure imgf000057_0004
and
Figure imgf000057_0005
, wherein the heterocycle portion is optionally substituted with one or more R6. [00219] In some embodiments, for a compound or salt of Formula (II), R2 is selected from -L- saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R6, and contains one nitrogen atom and one sulfur atom. In some cases, Y-R2 is selected from
Figure imgf000057_0006
, wherein the heterocycle portion is optionally substituted with one or more R6. In some cases, Y-R2 is selected from
Figure imgf000057_0007
, wherein the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3 alkyl and oxo. In some cases, Y-R2 is selected from
Figure imgf000058_0001
cases, Y-R2 is selected from
Figure imgf000058_0002
[00220] In some embodiments, for a compound or salt of Formula (II), each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1- C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo. [00221] In some embodiments, for a compound or salt of Formula (II), each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. [00222] In some embodiments, for a compound or salt of Formula (II), each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R5)2, and oxo. In some cases, each R6 is independently selected from -OH, Cl- C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, each R6 is independently selected from C1-C3 alkyl, C1-C3 alkoxy, and -N(R5)2. [00223] In some embodiments, for a compound or salt of Formula (II), R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. In some cases, R6 is selected from halogen and C1-C3 alkyl. In some cases, R6 is halogen. In some cases, R6 is C1-C3 alkyl. In some cases, R6 is selected from halogen and C1-C3 alkyl. In some cases, R6 is selected from methyl and fluorine. [00224] In some embodiments, for a compound or salt of Formula (II), R2 is selected from
Figure imgf000058_0003
[00225] In some embodiments, for a compound or salt of Formula (II), Y-R2 is selected from
Figure imgf000059_0001
[00226] In some embodiments, for a compound or salt of Formula (II), Y-R2 is selected from
Figure imgf000059_0002
[00227] In some embodiments, for a compound or salt of Formula (II), Y-R2 is
Figure imgf000059_0003
. [00228] In some embodiments, for a compound or salt of Formula (II), Y-R2 is selected from , and
Figure imgf000059_0004
. [00229] In some embodiments, for a compound or salt of Formula (II), L is selected from C1- C4 alkylene. [00230] In some embodiments, for a compound or salt of Formula (II), L is selected from unsubstituted C1-C4 alkylene. [00231] In some embodiments, for a compound or salt of Formula (II), R2 is -L-heterocycle, optionally substituted with one or more R6, wherein the heterocycle portion is a bicyclic heterocycle. In some cases, the bicyclic heterocycle contains at least 1 nitrogen atom. In some cases, the bicyclic heterocycle contains at most 1 nitrogen atom. [00232] In some embodiments, for a compound or salt of Formula (II), R2 is selected from L- bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R6. [00233] In some embodiments, for a compound or salt of Formula (II), R2 is selected from L- pyrrolizine, wherein the pyrrolizine is optionally substituted with one or more R6. [00234] In some embodiments, for a compound or salt of Formula (II), Y-R2 is selected from
Figure imgf000060_0001
, wherein the heterocycle portion is optionally substituted with one or more R6. [00235] In some embodiments, for a compound or salt of Formula (II), R6 of R2 is independently selected at each occurrence from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl. In some cases, R6 of R2 is independently selected at each occurrence from C1-C3 alkyl and halogen. In some cases, Y-R2 is
Figure imgf000060_0002
[00236] In some embodiments, for a compound or salt of Formula (II), M is selected from NR3. In some cases, M is selected from NH and NMe. In some cases, M is selected from NMe and NCH2CH3. In some cases, M is NMe. In some cases, M is selected from C1-6 cyanoalkyl. In some cases, M is selected from C2 cyanoalkyl. In some cases, M is selected from NH. In some cases, R3 is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkoxyalkyl, and C1-6 haloalkyl. In some cases, R3 is selected from hydrogen, C1-6 alkyl, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkoxyalkyl, and C1-6 haloalkyl. In some cases, R3 is selected from C1-6 alkyl, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkoxyalkyl, and C1-6 haloalkyl. In some cases, R3 is selected from C2-6 alkyl, C1-6 alkyl- N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkoxyalkyl, and C1- 6 haloalkyl. In some cases, R3 is selected from C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1- 6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkoxyalkyl, and C1-6 haloalkyl. In some cases, R3 is selected from C1-6 cyanoalkyl, C1-6 alkoxyalkyl, and C1-6 haloalkyl. In some cases, R3 is selected from hydrogen, C1-6 alkyl, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 haloalkyl. In some cases, R3 is selected from C1-6 alkoxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, R3 is
Figure imgf000060_0003
. In some cases, R3 is selected from C2-6 alkyl. [00237] In some embodiments, for a compound or salt of Formula (II), M is NR3, B is selected from
Figure imgf000060_0004
, each of which is optionally substituted; n is 0; Y is O; R2 is selected from L-heterocycle, wherein the heterocycle is optionally substituted with one or more R6; R1 is
Figure imgf000061_0006
, which is optionally substituted with one or more substituents independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, - C(O)NR20OR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases,
Figure imgf000061_0001
. some cases,
Figure imgf000061_0002
. In some cases,
Figure imgf000061_0003
heterocycle of L-heterocycle is bicyclic. In some cases, the heterocycle of L-heterocycle is monocyclic. In some cases, L is selected from an C1-C4 alkylene. In some cases, L is selected from an unsubstituted C1-C4 alkylene. In some cases, L is independently selected from a substituted C1-C4 alkylene, wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, Y-R2 is selected from
Figure imgf000061_0004
,
Figure imgf000061_0005
Figure imgf000062_0001
, which is substituted with one or more substituents. In some cases,
Figure imgf000062_0002
, which is substituted with one or more substituents. In some cases, B is selected from
Figure imgf000062_0003
, which is substituted with one or more substituents. In some cases, for B, the one or more substituents are independently selected from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, -OH, - C(O)NH2, -NH2, =O, -CN, -O-C1-C3 haloalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl. In some cases, B is substituted with at least one halogen. In some cases, B is substituted with at least one chlorine. In some cases, B is substituted with at least one fluorine. In some
Figure imgf000062_0004
-O-C1-C3 haloalkyl, and C1-6 haloalkyl. In some cases,
Figure imgf000062_0005
, which is substituted with one or more substituents selected from halogen. In some cases, B is selected from
Figure imgf000063_0001
,
Figure imgf000063_0002
, which is substituted with one or more substituents selected from fluorine. In some cases, B is
Figure imgf000063_0003
substituted with one or more substituents selected from chlorine. In some cases, B is selected from
Figure imgf000063_0004
. some cases, R3 is selected from hydrogen and C1-6 alkyl. In some cases, R3 is selected from C1-6 alkyl. In some cases, R3 is methyl. In some cases, each R6 is selected from halogen, oxo, and C1-6 alkyl. In some cases, each R6 is selected from halogen, and C1-6 alkyl. In some cases, each R6 is selected from halogen. In some cases, R1 is selected from
Figure imgf000063_0006
. [00238] In some embodiments, a compound is represented by the structure of Formula (III):
Figure imgf000063_0005
Formula (III) or a pharmaceutically acceptable salt thereof wherein: R1 is selected from C3-C12 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; R2 is selected from -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L- OC(O)N(R21)2, and L-bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R6; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; n is selected from 0 to 3; each R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, hydroxyl, halogen, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; B is selected from a heterocycle and carbocycle, wherein the heterocycle or carbocycle is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2- C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, C1-6 alkyl-N(R20)2, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; Y is selected from a bond, O, S and NR5; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1- C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; each R20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R21 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; and each R5 is independently selected from hydrogen or C1-C6 alkyl. [00239] In some embodiments, for a compound or salt of Formula (III), R1 is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, - S(O)2(R20), -C(O)N(R20)2, -C(O)NR20-OR20, -S(O)2N(R20)2, -NR20S(O)2R20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =NO(R20), -CN, -NHCN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. [00240] In some embodiments, for a compound or salt of Formula (III), R2 is selected from -L- NR21S(O)2(R21) and -L-S(O)2N(R21)2. [00241] In some embodiments, for a compound or salt of Formula (III), R2 is selected from -L- N(R21)C(O)(OR21), and -L-OC(O)N(R21)2. [00242] In some embodiments, for a compound or salt of Formula (III), each R21 is independently selected from hydrogen; C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O- C1-10 alkyl, and oxo. In some cases, each R21 is independently selected from hydrogen; C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R21 is independently selected from hydrogen and C1-6 alkyl. [00243] In some embodiments, for a compound or salt of Formula (III), R2 is selected from L- bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R6. [00244] In some embodiments, for a compound or salt of Formula (III), R2 is selected from L- pyrrolizine, wherein the pyrrolizine is optionally substituted with one or more R6. [00245] In some embodiments, for a compound or salt of Formula (III), B is an optionally substituted 5- to 15-membered heterocycle or optionally substituted C3-C15 carbocycle. In some cases, B is an optionally substituted 5- to 15-membered heterocycle. In some cases, B is an optionally substituted 8- to 15-membered heterocycle. In some cases, B is an optionally substituted C3-C15 carbocycle. In some cases, B is an optionally substituted C8-C15 carbocycle. [00246] In some embodiments, for a compound or salt of Formula (III), B is an optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted C8-C15 fused carbocycle. [00247] In some embodiments, for a compound or salt of Formula (III), for B, the optionally substituted 8- to 15-membered heterocycle contains at least one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least two heteroatoms. [00248] In some embodiments, for a compound or salt of Formula (III), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15- membered fused heterocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle are each bicyclic or tricyclic. [00249] In some embodiments, for a compound or salt of Formula (III), B the heterocycle or carbocycle are each independently bicyclic. In some cases, the heterocycle is bicyclic. In some cases, the carbocycle is bicyclic. [00250] In some embodiments, for a compound or salt of Formula (III), B the heterocycle or carbocycle are each independently tricyclic. In some cases, the heterocycle is tricyclic. In some cases, the carbocycle is tricyclic. [00251] In some embodiments, for a compound or salt of Formula (III), B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from
Figure imgf000067_0001
Figure imgf000067_0002
, each of which is optionally substituted with one or more substituents. [00252] In some embodiments, for a compound or salt of Formula (III), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from
Figure imgf000067_0003
,
Figure imgf000067_0004
[00253] In some embodiments, for a compound or salt of Formula (III), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from,
Figure imgf000068_0001
, each of which is optionally substituted with one or more substituents. [00254] In some embodiments, for a compound or salt of Formula (III), for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, C1-C3 alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, - NHCN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3 alkyl, -B(OR20)2, -OH, -C(O)N(R20)2, =O, -CN, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, - OH, -C(O)NH2, -NH2, =O, -CN, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from oxo, -NH2, -CN, halogen, C1-C3 alkyl. In some cases, the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH2, halogen, C1-C3 alkyl. [00255] In some embodiments, for a compound or salt of Formula (III), B is selected from
Figure imgf000068_0002
, , , , , ,
Figure imgf000069_0001
[00256] In some embodiments, for a compound or salt of Formula (III), for B, the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH2, halogen, C1-C3 alkyl. [00257] In some embodiments, for a compound or salt of Formula (III), B is selected from
Figure imgf000069_0002
. [00258] In some embodiments, for a compound or salt of Formula (III), each R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, hydroxyl, halogen. Ins some cases, each R4 is independently selected from C1-6 alkyl, oxo, and halogen. [00259] In some embodiments, for a compound or salt of Formula (III), n is selected from 1 and 2. In some cases, n is 0. [00260] In some embodiments, for a compound or salt of Formula (III), Y is O. [00261] In some embodiments, for a compound or salt of Formula (III), R1 is selected from optionally substituted 5- to 12-membered heterocycle. [00262] In some embodiments, for a compound or salt of Formula (III), R1 is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, SR20, - S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20,-N(R20)2, -C(O)R20, C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =NO(R20), CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1- 6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. [00263] In some embodiments, for a compound or salt of Formula (III), R1 is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, SR20, - S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20,-N(R20)2, -C(O)R20, C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =NO(R20), CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. [00264] In some embodiments, for a compound or salt of Formula (III), R1 is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -N(R20)C(O)OR20, and -OC(O)N(R20)2. [00265] In some embodiments, for a compound or salt of Formula (III), R1 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, - NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. [00266] In some embodiments, for a compound or salt of Formula (III), R1 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, - NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. [00267] In some embodiments, for a compound or salt of Formula (III), R20 of R1 is selected from hydrogen and C1-3 alkyl. [00268] In some embodiments, for a compound or salt of Formula (III), the 5- to 12-membered heterocycle of R1 is an unsaturated heterocycle. [00269] In some embodiments, for a compound or salt of Formula (III), the 5- to 12-membered heterocycle of R1 is a saturated heterocycle. [00270] In some embodiments, for a compound or salt of Formula (III), 5- to 12-membered heterocycle of R1 is a bridged heterocycle. [00271] In some embodiments, for a compound or salt of Formula (III), R1 is selected from
Figure imgf000070_0001
,
Figure imgf000071_0001
Figure imgf000071_0002
, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, =O, -CN, C1-6 hydroxyalkyl, and C1-6 haloalkyl. [00272] In some embodiments, for a compound or salt of Formula (III), R1 is selected from
Figure imgf000071_0003
f which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, - NO2, C1-6 aminoalkyl, C1-6 alkoxy, =O, -CN, C1-6 hydroxyalkyl, and C1-6 haloalkyl. [00273] In some embodiments, for a compound or salt of Formula (III), R1 is selected from
Figure imgf000071_0004
[00274] In some embodiments, for a compound or salt of Formula (III), R1 is selected from an optionally substituted saturated 6- to 7-membered heterocycle. In some cases, R1 is selected from an optionally substituted saturated 6-membered heterocycle. In some cases, R1 is selected from
Figure imgf000071_0005
, which is optionally substituted. In some cases, the optional one or more substituents are independently selected from halogen, -CN, -NHCN, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, the optional one or more substituents are independently selected from -NHCN, and C1-6 alkyl. In some cases, R1 is selected from , which is substituted with one or more substituents selected from -NHCN, and C1-6 alkyl. In some cases, R1 is selected from
Figure imgf000072_0001
, and
Figure imgf000072_0002
. [00275] In some embodiments, for a compound or salt of Formula (III), R1 is selected from a substituted saturated 6-membered heterocycle, wherein the saturated 6-membered heterocycle is substituted with at least one -NHCN, and optionally one or more C1-6 alkyl; M is O; n is 0; B is selected from an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15 fused carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, oxo, -NH2, C1-C3 alkyl, -OH, -C(O)NH2, - NH2, =O, -CN, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl; Y is O; R2 is selected from -L- bicyclic heterocycle, wherein the bicyclic heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R5)2; and L is selected from C1-C4 alkylene. In some
Figure imgf000072_0003
s
Figure imgf000073_0001
, . [00276] In some embodiments, for a compound or salt of Formula (III), L is selected from C1- C4 alkylene. [00277] In some embodiments, for a compound or salt of Formula (III), each L is independently selected from an optionally substituted C1-C4 alkylene; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, - NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6 haloalkyl. [00278] In some embodiments, for a compound or salt of Formula (III), each L is independently selected from a substituted C1-C4 alkylene, wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. [00279] In some embodiments, for a compound or salt of Formula (III), wherein each L is independently selected from a substituted C1-C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, each L is independently selected from a substituted C3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle. In some cases, each L is independently selected from
Figure imgf000073_0002
. [00280] In some embodiments, for a compound or salt of Formula (III), R2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. In some cases, the heterocycle is a saturated heterocycle. In some cases, the heterocycle has at least one nitrogen atom and at least one sulfur atom. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom. [00281] In some embodiments, for a compound or salt of Formula (III), R2 is selected from
Figure imgf000074_0001
wherein the heterocycle portion is optionally substituted with one or more R6. [00282] In some embodiments, for a compound or salt of Formula (III), Y-R2 is selected from
Figure imgf000074_0002
, wherein the heterocycle portion is optionally substituted with one or more R6. [00283] In some embodiments, for a compound or salt of Formula (III), Y-R2 is selected from
Figure imgf000074_0003
, , wherein the heterocycle portion is optionally substituted with one or more R6. [00284] In some embodiments, for a compound or salt of Formula (III), Y-R2 is selected from
Figure imgf000074_0004
[00285] In some embodiments, for a compound or salt of Formula (III), R2 is selected from -L- saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R6, and contains one nitrogen atom and one sulfur atom. In some cases, Y-R2 is selected from
Figure imgf000074_0005
, wherein the heterocycle portion is optionally substituted with one or more R6. In some cases, Y-R2 is selected from
Figure imgf000074_0006
, , , wherein the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3 alkyl and oxo. In some cases, Y-R2 is selected from
Figure imgf000075_0001
cases, Y-R2 is selected from
Figure imgf000075_0002
[00286] In some embodiments, for a compound or salt of Formula (III), each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1- C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo. [00287] In some embodiments, for a compound or salt of Formula (III), each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. [00288] In some embodiments, for a compound or salt of Formula (III), each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R5)2, and oxo. In some cases, each R6 is independently selected from -OH, Cl- C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, each R6 is independently selected from C1-C3 alkyl, C1-C3 alkoxy, and -N(R5)2. [00289] In some embodiments, for a compound or salt of Formula (III), R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. In some cases, R6 is selected from halogen and C1-C3 alkyl. In some cases, R6 is halogen. In some cases, R6 is C1-C3 alkyl. In some cases, R6 is selected from halogen and C1-C3 alkyl. In some cases, R6 is selected from methyl and fluorine. [00290] In some embodiments, for a compound or salt of Formula (III), R2 is selected from
Figure imgf000075_0003
[00291] In some embodiments, for a compound or salt of Formula (III), Y-R2 is selected from
Figure imgf000076_0001
[00292] In some embodiments, for a compound or salt of Formula (III), Y-R2 is selected from
Figure imgf000076_0002
[00293] In some embodiments, for a compound or salt of Formula (III), Y-R2 is
Figure imgf000076_0003
. [00294] In some embodiments, for a compound or salt of Formula (III), L is selected from unsubstituted C1-C4 alkylene. [00295] In some embodiments, for a compound or salt of Formula (III), Y-R2 is selected from
Figure imgf000076_0004
, wherein the heterocycle portion is optionally substituted with one or more R6. [00296] In some embodiments, for a compound or salt of Formula (III), R6 of R2 is independently selected at each occurrence from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl. [00297] In some embodiments, for a compound or salt of Formula (III), R6 of R2 is independently selected at each occurrence from C1-C3 alkyl and halogen. [00298] In some embodiments, for a compound or salt of Formula (III), Y-R2 is selected from
Figure imgf000076_0005
. [00299] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the carbocycle of R1 is selected from C3-C12 carbocycle, C3-C10 carbocycle, C3-C9 carbocycle, C3-C8 carbocycle, or C3-C6 carbocycle. In some cases, the carbocycle of R1 is selected from C3-C12 carbocycle, C4-C12 carbocycle, C5-C12 carbocycle, C6-C12 carbocycle, C7-C12 carbocycle, C8-C12 carbocycle, or C9-C12 carbocycle. [00300] In some embodiments, for a compound of Formula (I), the heterocycle of R1 is a 5- to 12-membered heterocycle, 6- to 12-membered heterocycle, 7- to 12-membered heterocycle, or 8- to 12-membered heterocycle. In some cases, the heterocycle of R1 is a 5- to 11-membered heterocycle, 5- to 10-membered heterocycle, 5- to 9-membered heterocycle, or 5- to 8-membered heterocycle. In some cases, the heterocycle of R1 is a 6- to 11-membered heterocycle, 6- to 10- membered heterocycle, 6- to 9-membered heterocycle, or 6- to 8-membered heterocycle. In some cases, the heterocycle of R1 is a 7- to 11-membered heterocycle, 7- to 10-membered heterocycle, 7- to 9-membered heterocycle, or 7- to 8-membered heterocycle. In some cases, the heterocycle of R1 is a 5- to 6-membered heterocycle or 5- to 9-membered heterocycle. In some cases, the heterocycle of R1 is an 8- to 9-membered heterocycle. In some cases, the heterocycle of R1 is saturated. The heterocycle may be optionally substituted as described elsewhere herein. [00301] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the heterocycle of R1 is a 5- to 12-membered monocyclic heterocycle, 6- to 12-membered monocyclic heterocycle, 7- to 12-membered monocyclic heterocycle, or 8- to 12-membered monocyclic heterocycle. In some cases, the heterocycle of R1 is a 5- to 11-membered monocyclic heterocycle, 5- to 10-membered monocyclic heterocycle, 5- to 9-membered monocyclic heterocycle, or 5- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R1 is a 6- to 11-membered monocyclic heterocycle, 6- to 10-membered monocyclic heterocycle, 6- to 9-membered monocyclic heterocycle, or 6- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R1 is a monocyclic 7- to 11-membered heterocycle, 7- to 10-membered monocyclic heterocycle, 7- to 9-membered monocyclic heterocycle, or 7- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R1 is a 5- to 6-membered monocyclic heterocycle or 5- to 9-membered monocyclic heterocycle. In some cases, the heterocycle of R1 is an 8- to 9-membered monocyclic heterocycle. In some cases, the heterocycle of R1 is saturated. The monocyclic heterocycle may be optionally substituted as described elsewhere herein. [00302] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the heterocycle of R1 is a 5- to 12-membered bridged heterocycle, 6- to 12-membered bridged heterocycle, 7- to 12-membered bridged heterocycle, or 8- to 12-membered bridged heterocycle. In some cases, the heterocycle of R1 is a 5- to 11-membered bridged heterocycle, 5- to 10-membered bridged heterocycle, 5- to 9-membered bridged heterocycle, or 5- to 8- membered bridged heterocycle. In some cases, the heterocycle of R1 is a 6- to 11-membered bridged heterocycle, 6- to 10-membered bridged heterocycle, 6- to 9-membered bridged heterocycle, or 6- to 8-membered bridged heterocycle. In some cases, the heterocycle of R1 is a bridged 7- to 11-membered heterocycle, 7- to 10-membered bridged heterocycle, 7- to 9- membered bridged heterocycle, or 7- to 8-membered bridged heterocycle. In some cases, the heterocycle of R1 is a 5- to 6-membered bridged heterocycle or 5- to 9-membered bridged heterocycle. In some cases, the heterocycle of R1 is an 8- to 9-membered bridged heterocycle. In some embodiments, the heterocycle of R1 is saturated. The bridged heterocycle may be optionally substituted as described elsewhere herein. [00303] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is a 5- to 9-membered heterocycle, the 5- to 9- membered heterocycle contains at most 1 nitrogen atom. In some embodiments, R1 is selected from optionally substituted 5- to 9- membered heterocycle, each of which is optionally substituted. [00304] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the heterocycle of R1 contains at most 1 nitrogen atom. In some embodiments, the heterocycle of R1 contains at most 1 heteroatom atom. In some embodiments, the heterocycle of R1 contains at most 2 heteroatom atoms. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some cases, the heterocycle is a monocyclic heterocycle or a bridged heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle is a bridged heterocycle. In some cases, the heterocycle is selected from
Figure imgf000078_0001
Figure imgf000078_0003
. In some cases, the heterocycle is selected from
Figure imgf000078_0002
, , , , and
Figure imgf000078_0004
. In some cases, the bridged heterocycle is selected from
Figure imgf000078_0005
, , . The heterocycle may be optionally substituted as described elsewhere herein. [00305] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the spiroheterocycle of R1 contains at most 1 nitrogen atom. In some embodiments, the spiroheterocycle of R1 contains at most 2 heteroatom atoms. In some embodiments, the spiroheterocycle of R1 contains at most 3 heteroatom atoms. In some embodiments, the spiroheterocycle of R1 contains at most 1 heteroatom atom. In some cases, the spiroheterocycle of R1 contains at least 2 heteroatom atoms. In some cases, the spiroheterocycle of R1 contains at least 3 heteroatom atoms. In some cases, the spiroheterocycle of R1 contains at least 4 heteroatom atoms. In some cases, the spiroheterocycle of R1 contains at least 2 nitrogen atoms. In some embodiments, the spiroheterocycle of R1 contains at most 1 heteroatom atom. In some cases, the spiroheterocycle of R1 contains at most 1 sulfur atom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some embodiments, the spiroheterocycle of R1 is
Figure imgf000079_0001
some embodiments, the spiroheterocycle of R1 is selected from
Figure imgf000079_0002
The spiroheterocycle may be optionally substituted as described elsewhere herein. [00306] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from optionally substituted 7- to 8-membered spiroheterocycle. In some cases, R1 is selected from optionally substituted 7-membered spiroheterocycle. In some cases, R1 is selected from optionally substituted 8-membered spiroheterocycle. [00307] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the fused heterocycle of R1 is a 6- to 12-membered fused heterocycle, 6- to 12-membered fused heterocycle, 7- to 12-membered fused heterocycle, or 8- to 12-membered fused heterocycle. In some cases, the fused heterocycle of R1 is a 6- to 11-membered fused heterocycle, 6- to 10-membered fused heterocycle, 6- to 9-membered fused heterocycle, or 6- to 8-membered fused heterocycle. In some cases, the fused heterocycle of R1 is a 7- to 11- membered fused heterocycle, 7- to 10-membered fused heterocycle, 7- to 9-membered fused heterocycle, or 7- to 8-membered fused heterocycle. In some cases, the fused heterocycle of R1 is an 8- to 11-membered fused heterocycle. In some cases, the fused heterocycle of R1 is a 6- membered fused heterocycle. The fused heterocycle may be optionally substituted as described elsewhere herein. [00308] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the fused heterocycle of R1 is selected from a 6-, 9-, 10-, 11-, and 12-membered fused heterocycle. In some cases, the fused heterocycle of R1 is selected from a 9- to 12-membered fused heterocycle. In some cases, the fused heterocycle of R1 is selected from a 10- to 12- membered fused heterocycle. The fused heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, =O, C1-6 aminoalkyl, C1-6 alkoxy,C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. The fused heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy,C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. [00309] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the fused heterocycle of R1 contains at most 1 nitrogen atom. In some embodiments, the fused heterocycle of R1 contains at most 1 heteroatom atom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some cases, the fused heterocycle i
Figure imgf000080_0001
. fused heterocycle may be optionally substituted as described elsewhere herein. [00310] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from C6-C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which is optionally substituted. [00311] In some embodiments, for a compound of Formula (I), R1 is selected from C6-C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 8- to 12- membered fused heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, =O, C1-6 aminoalkyl, C1-6 alkoxy,C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. [00312] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from C6-C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 8- to 12-membered fused heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. [00313] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), for R1, R20 of -OR20 and -N(R20)2, is selected hydrogen and C1-6 alkyl. [00314] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from C6-C7 carbocycle and 5- to 10-membered heterocycle, each of which is optionally substituted. In some cases, the heterocycle contains at most 1 nitrogen atom. In some cases, R1 is selected from C6-C7 carbocycle, each of which is optionally substituted. [00315] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the one or more optional substituents of R1 are independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, - N(R20)C(O)N(R20)2, and C1-6 alkyl. [00316] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), one or more optional substituents of R1 are independently selected from halogen, -OR20, - N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, the one or more optional substituents of R1 are independently selected from -OR20, - N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 alkyl. In some cases, the one or more optional substituents of R1 are independently selected from -OR20, -N(R20)2, C1-6 aminoalkyl, and C1-6 hydroxyalkyl. In some cases, the one or more optional substituents of R1 are independently selected from -OR20, -N(R20)2, C1-6 aminoalkyl, C1-6 alkyl, and C1-6 hydroxyalkyl. In some cases, the one or more optional substituents of R1 are independently selected from -OR20, -N(R20)2, and C1-6 alkyl. In some cases, the one or more optional substituents of R1 are independently selected from -N(R20)C(O)N(R20)2. [00317] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R1 is further selected from 7-, 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle wherein the C3-C12 carbocycle, 5- to 12-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, are each optionally substituted with one or more substituents independently selected from halogen, - OR20, -SR20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, - C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. [00318] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R1 is further selected from 7-, 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle wherein the C3-C12 carbocycle, 5- to 12-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, are each optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, - OR20, -SR20, -N(R20) S(O)2(R20), -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. [00319] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from 5- to 10-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, and wherein each are optionally substituted with one or more substituents independently selected from halogen, - N(R20)2, C1-6 alkyl, -OR20, -N(R20)C(O)N(R20)2, -B(OR20)2, -N(R20)C(O)N(R20)2, =O, C1-6 hydroxyalkyl, halogen, -N(R20)C(O)R20, -N(R20) S(O)2(R20), and C1-6 aminoalkyl. [00320] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from 5- to 10-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, and wherein each are optionally substituted with one or more substituents independently selected from halogen, - N(R20)2, C1-6 alkyl, -OR20, -N(R20)C(O)N(R20)2, -B(OR20)2, C1-6 cyanoalkyl, -N(R20)C(O)N(R20)2, =O, C1-6 hydroxyalkyl, halogen, -N(R20)C(O)R20, -N(R20) S(O)2(R20), and C1-6 aminoalkyl. In ,
Figure imgf000082_0001
substituted with one or more substituents independently selected from halogen, -N(R20)2, C1-6 alkyl, -OR20, -N(R20)C(O)N(R20)2, -B(OR20)2, C1-6 cyanoalkyl, -N(R20)C(O)N(R20)2, =O, C1-6 hydroxyalkyl, halogen, -N(R20)C(O)R20, -N(R20) S(O)2(R20), and C1-6 aminoalkyl. In some cases, ,
Figure imgf000082_0002
, , , , , , ,
Figure imgf000083_0001
[00321] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from 5- to 10-membered heterocycle, wherein the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from - OR20, -N(R20)2, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, -N(R20)C(O)N(R20)2, - N(R20)C(O)R20, and -B(OR20)2. In some cases, R1 is selected from , , ,
Figure imgf000084_0001
, each of which is optionally substituted with one or more substituents independently selected from -OR20, -N(R20)2, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, - N(R20)C(O)N(R20)2, -N(R20)C(O)R20, and -B(OR20)2. [00322] In some embodiments, for a compound of Formula (I), Formula (II), or Formula (III),
Figure imgf000084_0004
[00323] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from 5- to 10-membered heterocycle, wherein the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from - N(R20)2, -OR20, and C1-6 alkyl. In some cases, the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from -OR20, and C1-6 alkyl. In some embodiments, for a compound of Formula (I), Formula (II), or Formula (III), R1 is selected from
Figure imgf000084_0002
, each of which is optionally substituted with one or more substituents independently selected from -OR20, and C1-6 alkyl. In some cases, R1 is selected
Figure imgf000084_0003
[00324] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula
Figure imgf000085_0003
Figure imgf000085_0001
, each of which are optionally substituted. [00325] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from
Figure imgf000085_0002
, each of which is optionally substituted with one or more substituents independently selected from -OH, -CN, oxo, C1-6 cyanoalkyl.
[00326] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula
Figure imgf000086_0001
[00327] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from
Figure imgf000086_0002
, , , each of which are optionally substituted. [00328] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from
Figure imgf000086_0003
each of which are optionally substituted. [00329] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula
Figure imgf000086_0004
Figure imgf000086_0005
, each of which are optionally substituted. [00330] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is which is optionally substituted. [00331] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula
Figure imgf000087_0001
Figure imgf000088_0001
[00332] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula
Figure imgf000088_0002
[00333] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), wherein the 5- to 12-membered heterocycle of R1 is unsaturated and a bridged heterocycle. In some cases, R1 is selected from an optionally substituted 7- to 8-membered unsaturated and bridged heterocycle. In some cases, R1 is selected from . [00334] In some embodiments, for a compound of Formula (I) or Formula (II), R1 is selected from 5- to 10-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, and wherein each are optionally substituted with one or more substituents independently selected from halogen, -N(R20)2, C1-6 alkyl, -OR20, - N(R20)C(O)N(R20)2, -B(OR20)2, C1-6 cyanoalkyl, -N(R20)C(O)N(R20)2, =O, C1-6 hydroxyalkyl, halogen, -N(R20)C(O)R20, -N(R20) S(O)2(R20), and C1-6 aminoalkyl; R3 is naphthalene, wherein naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C2-6 alkynyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl; R4 is selected from hydrogen, halogen or C1-C3 alkyl; Y is O; L is independently a C1-C4 alkylene; R2 is selected from -L-heterocycle, wherein the heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R5)2. In some cases, Y-R2 is selected from
Figure imgf000089_0001
wherein the heterocycle portion is optionally substituted. [00335] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from an optionally substituted 5- to 12-membered unsaturated heterocycle, wherein the heterocycle has as most one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at least one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at most one nitrogen atom. [00336] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from 6- to 7-membered heterocycle. In some cases, R1 is selected from 7- membered heterocycle. In some cases, R1 is selected from 6-membered heterocycle. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur. In some cases, the optionally one or more additional heteroatoms are selected from sulfur. In some cases, the optionally one or more additional heteroatoms are selected from oxygen. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms. In some cases, the 6- to 7- membered heterocycle is a non-aromatic 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle of R1 is bound to Formula (I) via the only 1 nitrogen atom. In some cases, the 6- to 7-membered heterocycle of R1 is bound to Formula (II) via the only 1 nitrogen atom. In some cases, the 6- to 7-membered heterocycle of R1 is bound to Formula (III) via the only 1 nitrogen atom. In some cases, R1 is selected from
Figure imgf000089_0002
, each of which is substituted. In some cases, R1 is selected from
Figure imgf000089_0003
,
Figure imgf000089_0004
, ,
Figure imgf000089_0005
, each of which is substituted. In some cases, the substituents of R1 are each selected from one or more halogen, -OR20, -SR20, -N(R20)2, -NHCN, - NO2, =O, -CN, C1-6 fluoroalkyl, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkenyl. In some cases, the substituents of R1 are each selected from one or more halogen, -OR20, -N(R20)2, -NHCN, =O, -CN, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, the substituents of R1 are each selected from one or more halogen, -OH, -NHCN, =O, -CN, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from C1-6 alkyl.
Figure imgf000090_0001
,
Figure imgf000090_0002
, each of which is optionally substituted. In some cases, R1 is selected from
Figure imgf000090_0003
, each of which is optionally substituted. In some cases, R1 is selected from , , , , each of which is optionally substituted. In some cases, the one or more optional substituents of R1 are each independently selected from fluorine, -OH, -C(O)NH2, -NH-C(O)-(C1-6 alkoxy), -NH-C(O)-(C1-6 hydroxyalkyl), -NH2, -NH(CN), =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R1 are each independently selected from halogen, -OH, -CN, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R1 are each independently selected from halogen, -OH, and -CN. In some cases, the one or more optional substituents of R1 are each independently selected from fluorine, -OH, -CN, C1-6 cyanoalkyl, C1-6 alkyl, oxo, and C2-6 alkynyl. In some cases, the one or more optional substituents of R1 are each independently selected from fluorine, -OH, -CN, C1-6
Figure imgf000091_0001
,
Figure imgf000092_0001
Figure imgf000093_0003
[00337] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. In some cases, R1 is selected from an optionally substituted unsaturated 6-membered heterocycle. In some cases, R1 is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, the heterocycle has 1 or 2 double bonds. In some cases, the heterocycle has only 1 double bond. In some cases, the heterocycle has only 2 double bonds. In some cases, R1 is selected from
Figure imgf000093_0001
wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R1 is
Figure imgf000093_0002
wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R1 is selected from
Figure imgf000094_0001
wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R1 is
Figure imgf000094_0002
Figure imgf000094_0004
. , . , ,
Figure imgf000094_0003
, wherein each is substituted with one or more substituents independently selected from halogen. [00338] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from an unsaturated 6- to 7-membered heterocycle, wherein the unsaturated 6- to 7-membered heterocycle is substituted with one or more substituents selected from halogen. In some cases, the unsaturated 6- to 7-membered heterocycle is substituted with at least one halogen. In some cases, the unsaturated 6- to 7-membered heterocycle is substituted with at only one halogen. In some cases, the unsaturated 7-membered heterocycle is substituted with one fluorine. In some cases, R1 is selected from an unsaturated 6-membered heterocycle, substituted with at least one halogen. In some cases, R1 is selected from an unsaturated 7-membered heterocycle,
Figure imgf000095_0001
[00339] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. In some cases, R1 is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, R1 is selected from
Figure imgf000096_0001
, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, - NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R1 is selected from
Figure imgf000096_0002
[00340] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from an optionally substituted 6-membered heterocycle. In some cases, the 6- membered heterocycle contains only 1 nitrogen atom. In some cases, the 6-membered heterocycle of R1 is bound to Formula (I) via the only 1 nitrogen atom. In some cases, the 6-membered heterocycle of R1 is bound to Formula (II) via the only 1 nitrogen atom. In some cases, the 6- membered heterocycle of R1 is bound to Formula (III) via the only 1 nitrogen atom. In some cases, R1 is selected from
Figure imgf000096_0003
, any of which is optionally substituted. In some cases, the one or more optional substituents of R1 are each independently selected from halogen, -OR20, - N(R20)2, =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R1 are each independently selected from fluorine, -OH, - NH2, -NH(CN), =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R1 are each independently selected from fluorine, - OH, -NH2, -NH(CN), =O, -CN, C1-6 hydroxyalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the 6-membered heterocycle is a partially unsaturated 6-membered heterocycle or a saturated 6- membered heterocycle. In some cases, the 6-membered heterocycle is partially unsaturated. In some cases, the 6-membered heterocycle is a saturated 6-membered heterocycle. In some cases, the 6-membered heterocycle is a monocyclic 6-membered heterocycle. In some cases, the 6- membered heterocycle is not a bridged heterocycle. In some cases, R1 is selected from
Figure imgf000096_0004
Figure imgf000097_0001
[00341] In some embodiments, for a compound of Formula (I), Formula (II), or Formula (III), R1 is selected from an optionally substituted 6-membered unsaturated heterocycle and 6- membered saturated heterocycle. [00342] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from
Figure imgf000097_0002
, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. [00343] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from
Figure imgf000097_0003
, wherein each is optionally substituted with one or more substituents independently selected from halogen, and C1-6 haloalkyl. [00344] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from
Figure imgf000097_0004
[00345] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from
Figure imgf000097_0005
, wherein each is optionally substituted two substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. [00346] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from
Figure imgf000098_0001
, wherein each is optionally substituted with two substituents independently selected from halogen, and C1-6 haloalkyl. In some cases, R1 is
Figure imgf000098_0002
. [00347] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III),R1 is selected from an optionally substituted 6- to 10-membered heterocycle. In some cases, the 6- to 10-membered heterocycle contains at least 1 nitrogen atom. In some cases, R1 is
Figure imgf000098_0003
Figure imgf000098_0004
, each of which is optionally substituted with one or more substituents independently selected from halogen, =O, -OH, -CN, -NHCN, -C(O)N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, each R20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, R1 is selected from
Figure imgf000099_0001
[00348] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III),R1 is selected from an optionally substituted 10-membered heterocycle. In some cases, the 10-membered heterocycle is a bicyclic heterocycle. In some cases, the 10-membered heterocycle is a spiro heterocycle. In some cases, the 10-membered heterocycle is a fused heterocycle. In some cases, the 10-membered heterocycle is a saturated heterocycle. In some cases, the 10-membered heterocycle is a non-aromatic heterocycle. In some cases, the 10- membered heterocycle contains at least 1 nitrogen atom. In some cases, the 10-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 3 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 1 sulfur atom. In some cases, R1 is selected from
Figure imgf000099_0002
, each of which is optionally substituted with one or more substituents independently selected from halogen, =O, -OH, -CN, -NHCN, -C(O)N(R20)2, -C(O)NR20OR20, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, R1 is selected from
Figure imgf000099_0003
,
Figure imgf000100_0001
some cases, R1 is selected from
Figure imgf000100_0002
. some cases, R1 is selected from
Figure imgf000100_0003
, which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -SR20, -N(R20)2, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. [00349] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from an optionally substituted unsaturated 9- to 11-membered heterocycle. In some cases, R1 is selected from an optionally substituted unsaturated 10- membered heterocycle. In some cases, R1 is selected from an optionally substituted unsaturated 10-membered fused heterocycle. In some cases,
Figure imgf000100_0004
, which is optionally substituted. In some cases, the one or more optional substituents are selected from halogen, - OH, -C(O)N(R20)2, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, R1 is
Figure imgf000101_0001
, optionally substituted with one or more substituents selected from - N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, each R20 is independently selected from hydrogen; and C1-6 alkyl, and C3-12 carbocycle, and each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. [00350] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from a 7- to 11-membered spiro heterocycle. In some cases, R1 is selected from a 10-membered spiro heterocycle. In some cases, the spiro heterocycle has at least 3 nitrogen atoms. In some cases, the spiro heterocycle has at least 1 sulfur atom. In some cases, R1 is selected from
Figure imgf000101_0002
, each of which is optionally substituted. In some cases, the one or more optional substituents are independently selected from halogen, -OH, - N(R20)2, -NO2, =O, -CN, -NHCN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, R1 is selected
Figure imgf000101_0003
some cases, R1 is
Figure imgf000101_0004
. some cases, M is selected from O, and NR3. In some cases, M is selected from O. In some cases, M is selected from NR3. In some cases, R3 is selected from C1-6 alkyl. In some cases, R3 is selected from C1-2 alkyl. In some cases, R3 is selected from methyl. [00351] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III),R1 is selected from an optionally substituted 8- to 10-membered fused heterocycle. In some cases, the 8- to 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 8- to 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 8- to 10- membered fused heterocycle is an unsaturated heterocycle. In some cases, the 8- to 10- membered heterocycle is a non-aromatic heterocycle. In some cases, R1 is selected from an optionally substituted 9-membered fused heterocycle. In some cases, R1 is selected from an optionally substituted 10-membered fused heterocycle. In some cases, the 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 9-membered heterocycle is a non-aromatic heterocycle. In some cases, the 10-membered heterocycle is a non-aromatic heterocycle. In some cases, the fused heterocycle has one saturated ring and one aromatic ring. In some cases, the fused heterocycle has one saturated ring and one unsaturated ring. In some cases, the fused heterocycle has two saturated rings. In some cases, the 10-membered heterocycle contains at least 1 nitrogen atom. In some cases, the 10-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 3 nitrogen atoms. In some cases, the 9- membered heterocycle contains at least 1 nitrogen atom. In some cases, the 9-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 9-membered heterocycle contains at least 3 nitrogen atoms. In some cases, R1 is selected from
Figure imgf000102_0001
, each of which is optionally substituted with one or more substituents. In some cases, R1 is
Figure imgf000102_0002
, which is optionally substituted with one or more substituents. In some cases, R1 is
Figure imgf000102_0003
, which is optionally substituted with one or more substituents. In some cases, the one or more optional substituents of R1 are independently selected from halogen, -OH, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(=NR20)N(R20)2, -C(O)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkynyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*. In some cases, the one or more optional substituents of R1 are independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6 alkyl- N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the optional one or more substituents are independently selected from halogen, =O, -OH, -CN, -NHCN, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)R20, -C(O)N(R20)2, -C(O)NR20OR20, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, the optional one or more substituents are independently selected from halogen, =O, C1-6 alkyl-N(R20)2, -S(O)2(R20), - S(O)N(R20)2, -S(O)R20(=NR20), -C(O)R20, -C(O)N(R20)2, and -C(O)NR20OR20. In some cases, the optional one or more substituents are independently selected from halogen, =O, -S(O)2(R20), -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)R20, -C(O)N(R20)2, and -C(O)NR20OR20. In some cases, the optional one or more substituents are independently selected from -C(O)R20, -C(O)N(R20)2, and -C(O)NR20OR20. In some cases, the optional one or more substituents are independently selected from -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20). In some cases, the optional one or more substituents are independently selected from -S(O)N(R20)2. In some cases, the optional one or more substituents are independently selected from S(O)2(R20). In some cases, the optional one or more substituents are independently selected from S(O)R20(=NR20). In some cases, the optional one or more substituents are independently selected from -C(O)R20. In some cases, the optional one or more substituents are independently selected from -C(O)N(R20)2. In some cases, the optional one or more substituents are independently selected from - C(O)NR20OR20. In some cases, R1 is selected from
Figure imgf000103_0001
, ,
Figure imgf000103_0002
,
Figure imgf000104_0001
, each of which is further optionally substituted. In some cases, the further one or more optional substituents are selected from halogen, -OH, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the further one or more optional substituents are selected from halogen, -CN, C2 alkenyl, and C1-6 alkyl. In some cases, the further one or more optional substituents are selected from halogen, and C1-6 alkyl. In some cases, the further one or more optional substituents are selected from halogen. In some cases, each R20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20 is independently selected from hydrogen; and C1-6 alkyl, and 3- to 12- membered heterocycle. In some cases, each R20 is independently selected from hydrogen; and C1-6 alkyl, and 3- to 12-membered saturated heterocycle. In some cases, each R20 is independently selected from 5- to 6-membered saturated heterocycle. In some cases, the heterocycle of R20 has at least one nitrogen atom. In some cases, the heterocycle of R20 has at least one sulfur atom. In some cases, the heterocycle of R20 has at least one oxygen atom. In some cases, the heterocycle of R20 contains only 1 heteroatom. In some cases, the heterocycle of R20 has at least two heteroatoms. In some cases, the heterocycle of R20 contains only 2 heteroatoms. In some cases, the optional one or more substituents of R1 are independently
Figure imgf000104_0002
optional one or more substituents of R1 are independently selected from halogen,
Figure imgf000104_0003
,
Figure imgf000104_0004
,
Figure imgf000105_0001
some cases, the optional one or more substituents of R1 are
Figure imgf000105_0002
or more substituents of R1 are independently selected from
Figure imgf000105_0003
Figure imgf000105_0004
,
Figure imgf000106_0001
Figure imgf000107_0001
more substituents of R1 are independently selected from halogen, and C1-6 alkyl-N(R20)2. In some cases, the optional one or more substituents of R1 are independently selected from halogen,
Figure imgf000107_0004
. , ydrogen, C1-6 alkyl, and C3-6 carbocycle. In some cases, R1 is selected
Figure imgf000107_0002
,
Figure imgf000107_0003
some cases, R1 is selected
Figure imgf000108_0001
selected from , which is optionally substituted with one more substituents independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)OR20, -C(O)NHOR20, -N(R20)2, - C(O)R20, -NO2, =O, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OR20, and C1-6 alkyl. In some cases, R1 is selected
Figure imgf000108_0002
from , which is optionally substituted with one more substituents independently selected from halogen and C1-6 alkyl. In some cases, R1 is selected from
Figure imgf000109_0001
Figure imgf000109_0002
. [00352] In some embodiments, for a compound or salt of Formula (I), Formula (II), or
Figure imgf000109_0003
selected from a 5- to 12- membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1* ; and RB is selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, and -CN. In some cases, RB is selected from hydrogen, and halogen. In some cases, RB is chloride. In some cases, RB is hydrogen. In some cases,
Figure imgf000109_0004
, 2, 3, or 4 heteroatoms. In some cases,
Figure imgf000109_0005
has at least 1, 2, 3, or 4 nitrogen atoms. In some cases,
Figure imgf000109_0006
has at least 1 oxygen atom. In some cases,
Figure imgf000109_0007
is a monocyclic heterocycle. In some cases,
Figure imgf000109_0008
is a bicyclic heterocycle. In some cases,
Figure imgf000109_0009
is selected from an optionally substituted 5-membered heterocycle. In some cases,
Figure imgf000109_0010
is selected from an optionally
Figure imgf000109_0011
substituted with one or more R1*. In some cases,
Figure imgf000109_0012
, ,
Figure imgf000110_0001
is optionally substituted with one or more R1*. In some cases, each R1* is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, each R1* is independently selected from halogen, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, each R1* is independently selected from halogen, and C1-6 alkyl. In some cases,
Figure imgf000110_0002
, , ,
Figure imgf000110_0003
[00353] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), when R1 is substituted with -C(O)R20, R20 is selected from a 5- to 12- membered heterocycle, which is optionally substituted. In some cases, R1 is substituted with - C(O)R20. In some cases, R20 is selected from a 5- to 12-membered unsubstituted heterocycle. In some cases, R20 is selected from a 5- to 6-membered heterocycle, which is optionally substituted. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom. In some cases, the heterocycle has at least one oxygen atom. In some cases, the heterocycle has two heteroatoms. In some cases, the heterocycle of R20 is selected
Figure imgf000110_0004
, each of which is optionally substituted. In some cases, R20 is selected from
Figure imgf000110_0005
some cases, the optional substituents are selected from C1-10 alkyl, oxo, and =NH. [00354] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), each R20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, and =NH. In some cases, each R20 is independently selected from hydrogen; and unsubstituted C1-6 alkyl, and 3- to 12-membered heterocycle which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, and =NH. [00355] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is an optionally substituted 12- to 15-membered heterocycle. In some cases, R1 is an optionally substituted 12-membered heterocycle. In some cases, R1 is an optionally substituted 13-membered heterocycle. In some cases, R1 is an optionally substituted 14- membered heterocycle. In some cases, R1 is an optionally substituted 15-membered heterocycle. In some cases, the heterocycle of R1 is tricyclic. In some cases, the heterocycle of R1 contains a fused heterocycle. In some cases, the heterocycle of R1 contains a spiro-heterocycle. In some cases, the heterocycle of R1 contains a fused and spiro-heterocycle. In some cases, the heterocycle of R1 is an unsaturated heterocycle. In some cases, the heterocycle of R1 is a non- aromatic heterocycle. In some cases, the heterocycle of R1 has at least one double bond. In some cases, the heterocycle of R1 has at least two double bonds. In some cases, the heterocycle of R1 has at least 2 heteroatoms. In some cases, the heterocycle of R1 has at least 3 heteroatoms. In some cases, the heterocycle of R1 has at least 4 heteroatoms. In some cases, the heterocycle of R1 has at least 5 heteroatoms. In some cases, the heterocycle of R1 has at least 6 heteroatoms. In some cases, the heterocycle of R1 has at least 7 heteroatoms. In some cases, the heteroatoms are selected from oxygen, nitrogen, and sulfur. In some cases, the heterocycle of R1 has at least 3, 4, or 5 nitrogen atoms, and at least 1 sulfur atom. In some cases, the heterocycle of R1 has at least 3, 4, or 5 nitrogen atoms, and at least 1 oxygen atom. In some cases, the heterocycle of R1 has at least 3, 4, or 5 nitrogen atoms. In some cases, the heterocycle of R1 has at least 3, 4, or 5 nitrogen atoms and no other heteroatoms. In some cases, the heteroatoms are selected from nitrogen and sulfur. In some cases, the heteroatoms are selected from nitrogen and oxygen. In
Figure imgf000111_0001
,
Figure imgf000112_0001
, each of which is optionally substituted with one or more substituents. In some cases, R1 is
Figure imgf000112_0002
, , , , ,
Figure imgf000112_0003
, each of which is optionally substituted with one or more substituents. In some cases, the optional one or more substituents of R1 are independently selected from halogen, -OH, -NHCN, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, =NH, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the optional one or more substituents of R1 are independently selected from halogen, -OH, -NHCN, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the optional one or more substituents of R1 are independently selected from halogen, -OH, C1-6 alkyl, and -C(O)N(R20)2. In some cases, R1 is selected from
Figure imgf000112_0004
,
Figure imgf000113_0001
[00356] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is an optionally substituted 12- to 15-membered heterocycle. In some cases, R1
Figure imgf000113_0002
, wherein Ring W is an optionally substituted heterocycle and Ring P is an optionally substituted carbocycle or optionally substituted heterocycle, wherein Ring P forms a spirocycle with Ring W. In some cases, Ring W is an optionally substituted fused heterocycle. In some cases, Ring P and Ring W combine to form a heterocycle having at least 12 atoms and most 15 atoms. In some cases, Ring P and Ring W have in total at least 12 atoms and most 15 atoms. In some cases, Ring W is an optionally substituted 10-membered fused heterocycle. In some cases,
Figure imgf000114_0001
, wherein Ring P is an optionally substituted carbocycle or optionally substituted heterocycle. In some cases,
Figure imgf000114_0002
. some cases, Ring P is an optionally substituted carbocycle. In some cases, Ring P is an optionally substituted heterocycle. In some cases, Ring P forms an optionally substituted C3-C6 carbocycle or optionally substituted 4-to 6-membered heterocycle. In some cases, Ring P forms an optionally substituted C3 carbocycle. In some cases, Ring P forms an optionally substituted C4 carbocycle. In some cases, Ring P forms an optionally substituted C5 carbocycle. In some cases, Ring P forms an optionally substituted 4-membered heterocycle. In some cases, Ring P forms an optionally substituted 5-membered heterocycle. In some cases, Ring P forms an optionally substituted 5-membered heterocycle. In some cases, Ring P has at least 1, 2, or 3 heteroatoms. In some cases, the heteroatoms are selected from oxygen, nitrogen, and sulfur. In some cases, Ring P has 1 sulfur atom. In some cases, Ring P has 1 nitrogen atom. In some cases, Ring P has 1 oxygen atom. In some cases, the one or more optional substituents of Ring P are independently selected from halogen, -OH, -NHCN, =O, =NR20, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of Ring P are independently selected from halogen, -OH, =O, =NH, -CN, and C1-6 alkyl. In some cases, the one or more optional substituents of Ring W are independently selected from halogen, -OH, -NHCN, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of Ring W are independently selected from halogen, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, - C(O)NR20OR20, -C(O)NHOR20, -N(R20)2, -C(O)R20, and C1-6 alkyl. In some cases, the one or more optional substituents of Ring W are independently selected from -C(O)R20. In some cases, Ring P is substituted. In some cases, Ring W is substituted. [00357] In some embodiments, for a compound or salt of Formula (I), Formula (II), or
Figure imgf000115_0001
Figure imgf000115_0002
, each of which is optionally substituted with one or more substituents. In some cases, the one or more of the optional substituents are independently selected from halogen, -OH, -N(R20)2, -B(OH)2, -C(O)N(R20)2, -NHCN, -NO2, C1-6 alkoxy, =O, -CN, C1-6 alkyl, C2-6 alkenyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, R1 is selected from
Figure imgf000115_0003
,
Figure imgf000116_0001
Figure imgf000117_0001
,
Figure imgf000117_0002
,
Figure imgf000117_0003
Figure imgf000118_0001
,
Figure imgf000119_0001
. [00358] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R2 is selected from optionally substituted -L-heterocycle. In some cases, the heterocycle is a bicyclic heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle has only 1 nitrogen atom. In some cases, the heterocycle has only 1 nitrogen atom and no other heteroatoms. In some cases, Y-R2 is selected from
Figure imgf000119_0002
Figure imgf000119_0005
substituted. In some cases, Y-R2 is selected from
Figure imgf000119_0003
, wherein the heterocycle portion is optionally substituted. In some cases, Y-R2 is selected from
Figure imgf000119_0004
, wherein the heterocycle portion is optionally substituted. In some cases, the heterocycle is optionally substituted with one or more substituent selected from halogen, hydroxy, C1-C3 alkyl, - N(R5)S(O)2(R5), -OC(O)N(R5)2, oxo, =CH2, =NO-C1-C3 alkyl, -CH2OC(O)heterocycle, - CH2heterocycle, -CH2OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy. In some
Figure imgf000120_0001
Figure imgf000121_0001
[00359] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R2 is selected from -L-N(R21)2. In some cases, each R21 is selected from hydrogen and C1-6 alkyl. In some cases, each R21 is selected from C1-6 alkyl. In some cases, L is independently selected from a substituted C1-C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen. In some cases,
Figure imgf000121_0002
. In some cases, R2 is
Figure imgf000121_0004
. In some cases, Y-R2 is
Figure imgf000121_0003
. [00360] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III),each R21 is independently selected from hydrogen. In some cases, each R21 is independently selected from hydrogen and C1-6 alkyl. In some cases, each R21 is independently selected from C1-6 alkyl. In some cases, each R21 is independently selected from hydrogen; and C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo. [00361] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III),R1 is selected from an optionally substituted 8- to 10-membered fused heterocycle. In some cases, the 8- to 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 8- to 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 8- to 10-membered heterocycle is a non-aromatic heterocycle. In some cases, R1 is selected from an optionally substituted 9-membered fused heterocycle. In some cases, R1 is selected from an optionally substituted 10-membered fused heterocycle. In some cases, the 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 10-membered heterocycle is a non-aromatic heterocycle. In some cases, the fused heterocycle has one saturated ring and one aromatic ring. In some cases, the fused heterocycle has one saturated ring and one unsaturated ring. In some cases, the fused heterocycle has two saturated rings. In some cases, the 10-membered heterocycle contains at least 1 nitrogen atom. In some cases, the 9-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 9-membered heterocycle contains at least 3 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 10- membered heterocycle contains at least 3 nitrogen atoms. In some cases, R1 is selected from
Figure imgf000122_0001
, which is optionally substituted with one or more substituents. In some cases, the optional one or more substituents are independently selected from halogen, =O, -OH, -CN, -NHCN, - C(O)R20, -C(O)N(R20)2, -C(O)NR20OR20, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, the optional one or more substituents are independently selected from halogen, =O, -C(O)R20, -C(O)N(R20)2, and -C(O)NR20OR20. In some cases, the optional one or more substituents are independently selected from -C(O)R20, -C(O)N(R20)2, and - C(O)NR20OR20. In some cases, the optional one or more substituents are independently selected from -C(O)R20. In some cases, the optional one or more substituents are independently selected from -C(O)N(R20)2. In some cases, the optional one or more substituents are independently selected from -C(O)NR20OR20. In some cases, each R20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20 is independently selected from hydrogen; and C1-6 alkyl, and 3- to 12-membered heterocycle. In some cases, each R20 is independently selected from hydrogen; and C1-6 alkyl, and 3- to 12- membered saturated heterocycle. In some cases, the optional one or more substituents of R1 are
Figure imgf000123_0001
Figure imgf000124_0001
[00362] In some embodiments, for a compound or salt of Formula (I), R1 is selected from an optionally substituted saturated 6- to 7-membered heterocycle. In some cases, R1 is selected from an optionally substituted saturated 6-membered heterocycle. In some cases, R1 is selected from , which is optionally substituted. In some cases, the optional one or more substituents are independently selected from halogen, -CN, -NHCN, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, the optional one or more substituents are independently selected from -NHCN, and C1-6 alkyl. In some cases, R1 is selected from , which is substituted with one or more substituents selected from -NHCN, and C1-6 alkyl. In some cases, R1 is selected from
Figure imgf000124_0002
, and
Figure imgf000124_0003
. [00363] In some embodiments, for a compound or salt of Formula (I), R1 is selected from a substituted saturated 6-membered heterocycle, wherein the saturated 6-membered heterocycle is substituted with at least one -NHCN, and optionally one or more C1-6 alkyl; B is selected from an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15 fused carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, oxo, -NH2, C1-C3 alkyl, -OH, -C(O)NH2, -NH2, =O, -CN, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl; Ring A is selected from an optionally substituted heterocycle; Y is O; R2 is selected from -L-heterocycle, wherein the heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R5)2; and L is selected from C1-C4 alkylene. In some cases, R1 is selected from
Figure imgf000125_0001
, and
Figure imgf000125_0002
[00364] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), B is an optionally substituted 8- to 10-membered fused carbocycle. In some cases, B is a substituted 8- to 10-membered fused carbocycle. In some cases, B is an unsubstituted 8- to 10- membered fused carbocycle. In some cases, B is an optionally substituted 9-membered fused carbocycle. In some cases, B is a substituted 9-membered fused carbocycle. In some cases, B is , which is optionally substituted with one or more substituents. In some cases, B is
Figure imgf000126_0001
, which is substituted with one or more substituents. In some cases, for B, the one or more substituents are independently selected from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, - OH, -C(O)NH2, -NH2, =O, -CN, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl. In some cases, B is substituted with at least one halogen. In some cases, B is substituted with at least one chlorine. In some cases, B is substituted with at least one fluorine. In some cases, B is selected
Figure imgf000126_0002
selected from halogen and C1-6 haloalkyl. In some cases,
Figure imgf000126_0003
, which is substituted with one or more substituents selected from halogen. In some cases, B is selected from
Figure imgf000126_0004
,
Figure imgf000126_0005
, which is substituted with one or more substituents selected from fluorine. In some cases, B is
Figure imgf000127_0001
substituted with one or more substituents selected from chlorine. In some cases, B is selected from
Figure imgf000127_0002
. some cases, B is a substituted 10-membered fused carbocycle. In some cases, for the 10-membered fused carbocycle of B, the one or more substituents are independently selected from halogen, -NH2, C1-C3 alkyl, -B(OH)2, -OH, - C(O)NH2, -NH2, =O, -CN, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl. In some cases, B is
Figure imgf000127_0003
In some cases, for the 10-membered fused carbocycle of B, is substituted with at least one
Figure imgf000127_0004
,
Figure imgf000127_0005
. some cases, B is an unsubstituted 9- to 10-membered fused carbocycle. In some cases, B is selected
Figure imgf000128_0001
, each of which is unsubstituted. In some cases,
Figure imgf000128_0002
. , . [00365] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the one or more optional substituents of R1 are independently selected from halogen, -OH, - S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, - C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, and C1-6 alkyl. [00366] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula
Figure imgf000128_0003
the one or more optional substituents of R1 are independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, - C(=NR20)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkynyl, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1 are independently selected from halogen, -OH, - S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, - C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkynyl, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1 are independently selected from halogen, -CN, C2-6 alkynyl, - C(=NR20)N(R20)2, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1 are independently selected from halogen, - C(=NR20)N(R20)2, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1 are independently selected from -C(=NR20)N(R20)2, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1 are independently selected from optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1 are independently selected from a 5-membered heterocycle and 9-membered heterocycle, each of which is optionally substituted independently with one or more R1*. In some cases, R1 is substituted with at least one halogen atom and optionally substituted with one or more substituents are independently selected from -CN, C2-6 alkynyl, -C(=NR20)N(R20)2, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least oxygen atom. In some cases, the heterocycle has at least one nitrogen atom and at least one oxygen atom. In some cases, heterocycle has at least two heteroatoms. In some cases, the heterocycle has at least three heteroatoms. In some cases, the heterocycle has at least four heteroatoms. In some cases, the heterocycle of the one or more optional substituents of R1 is selected from
Figure imgf000129_0001
,
Figure imgf000129_0002
optionally substituted with one or more R1*. In some cases, the heterocycle of the one or more optional substituents of R1 is selected from
Figure imgf000129_0003
, which is optionally substituted with one or more R1*. In some cases, each R1* is independently selected from halogen, -OR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, each R1* is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, each R1* is independently selected from halogen, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, each R1* is independently selected from halogen, C1-6 haloalkyl, and C1-6 alkyl. In some cases, each R1* is independently selected from halogen, and C1-6 alkyl. In some cases, each R1* is independently selected from halogen. In some cases, each R1* is independently selected from C1-6 alkyl. In some cases, each R1* is independently selected from -OR20. In some cases, each R1* is independently selected from -OH. In some cases, each R1* is independently selected from -OMe. In some cases, the heterocycle of the one or more optional substituents of R1 is selected from
Figure imgf000130_0001
[00367] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the one or more optional substituents of R1 are independently selected from - C(=NR20)N(R20)2, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1 are independently selected from optionally substituted 5- to 12-membered heterocycle. In some cases, the heterocycle is selected from
Figure imgf000130_0002
,
Figure imgf000130_0003
, each of which is optionally substituted with one or more R1*. In some cases, the one or more
Figure imgf000130_0004
[00368] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), each R1* is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, each R1* is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, each R1* is independently selected from halogen, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, each R1* is independently selected from halogen, C1-6 haloalkyl, and C1-6 alkyl. In some cases, each R1* is independently selected from halogen, and C1-6 alkyl. In some cases, each R1* is independently selected from halogen. In some cases, each R1* is independently selected from C1-6 alkyl. [00369] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from 5- to 15-membered heterocycle (preferably 8- to 10-membered heterocycle or preferably 10-membered heterocycle), each of which are optionally substituted with one or more substituents independently selected from halogen, oxo, -C(O)N(R20)2, - C(O)NR20OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -SO2R20, -NHCN, C1-6 cyanoalkyl, C1-6 alkyl, C1-6 alkyl-N(R20)2, C2-6 alkynyl, and 5- to 12-membered heterocycle (preferably 5- to 9- membered heterocycle), wherein the 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, C1-6 haloalkyl, and C1-6 alkyl. In some cases, the 8- to 10-membered heterocycle is bicyclic. In some cases, the 10-membered heterocycle is substituted. In some cases, R1 is
Figure imgf000131_0001
selected , , , , and , each of which is optionally substituted. In some
Figure imgf000131_0002
cases, R1 is selected , which is optionally substituted. In some cases, R1 is selected
Figure imgf000131_0003
,
Figure imgf000132_0001
[00370] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from 5- to 15-membered heterocycle (preferably 8- to 10-membered heterocycle or preferably 10-membered heterocycle), each of which are optionally substituted with one or more substituents independently selected from halogen, -C(O)N(R20)2, - C(O)NR20OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -NHCN, C1-6 cyanoalkyl, C1-6 alkyl, C2-6 alkynyl, and 5- to 12-membered heterocycle (preferably 5- to 6-membered heterocycle), wherein the 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, C1-6 haloalkyl, and C1-6 alkyl. In some cases, the 8- to 10-membered heterocycle is bicyclic. In some cases, the 10-membered heterocycle is substituted. In some cases, R1 is selected
Figure imgf000132_0002
, , , each of which is
Figure imgf000132_0003
optionally substituted. In some cases, R1 is selected , which is optionally substituted. In
Figure imgf000132_0004
Figure imgf000133_0001
some cases, M is selected from O, and NMe. In some cases, M is O. In some cases, M is NMe. In some cases, R2 is selected from -L-N(R21)2 and -L-heterocycle, optionally substituted with one or more R6. In some cases, Y-R2 is selected from
Figure imgf000133_0002
, ,
Figure imgf000133_0003
some cases, B is selected from an optionally substituted carbocycle. In some cases, B is selected from
Figure imgf000133_0004
substituted. In some cases, B is selected from
Figure imgf000133_0005
,
Figure imgf000133_0006
. , . [00371] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is selected from a compound in the Examples section. In some cases, Y is selected from a compound in the Examples section. In some cases, L is selected from a compound in the Examples section. In some cases, R2 is selected from a compound in the Examples section. In some cases, B is selected from a compound in the Examples section.. In some cases, M is selected from a compound in the Examples section. In some cases, the optional substituents of the heterocycle for R1 is selected from a compound in the Examples section. [00372] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R2 is -L-N(R21)2. In some cases, R2 is -L-OR21. In some cases, R2 is heterocycle. In some cases, R2 is C1-C6 alkyl. In some cases, R2 is -L-heterocycle. In some cases, R2 is -L-aryl. In some cases, R2 is -L-heteroaryl. In some cases, R2 is -L-cycloalkyl. In some cases, R2 is -L-N(R21)2. In some cases, R2 is -L-NHC(=NH)NH2. In some cases, R2 is -L-C(O)N(R21)2. In some cases, R2 is -L-C1-C6 haloalkyl. In some cases, R2 is -L-OR21. In some cases, R2 is -L-NR21C(O)-aryl. In some cases, R2 is -L-COOH. In some cases, R2 is -L-NR21S(O)2(R21). In some cases, R2 is -L- S(O)2N(R21)2. In some cases, R2 is -L-N(R21)C(O)(OR21). In some cases, R2 is -L-OC(O)N(R21)2. In some cases, R2 is or -LC(=O)OC1-C6 alkyl. In some cases, the heterocycle, the aryl portion of - L-NR21C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L- cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of the -L- aryl and the heteroaryl portion of the -L-heteroaryl are each optionally substituted with one or more R7. In some cases, when Y is a bond, O, or S, R2 is further selected from hydrogen [00373] In some embodiments, Formula (I) or Formula (II) is represented by Formula (II*):
Figure imgf000134_0001
Formula (II*) or a pharmaceutically acceptable salt thereof wherein: M is selected from O, and NR3; R3 is selected from hydrogen, C1-6 alkyl, and C1-6 cyanoalkyl; R1 is selected from a 7- to 10-membered heterocycle, wherein the 7- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; B is selected from C6-C15 carbocycle, wherein the C6-C15 carbocycle is optionally substituted with one or more substituents independently selected from halogen, C1-C3 alkyl, - B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; R2 is selected from -L-heterocycle, wherein the heterocycle of -L-heterocycle is optionally substituted with one or more R6; L is independently selected from a C1-C4 alkylene, wherein the C1-C4 alkylene is optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle; each R20 is independently selected from hydrogen; and C1-6 alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, =NH, C3-12 carbocycle, and 3- to 12-membered heterocycle. [00374] In some embodiments, for a compound or salt of Formula (II*), R1 is selected from an optionally substituted 7- to 10-membered spiro heterocycle and optionally substituted 7- to 10- membered fused heterocycle. In some cases, the heterocycle of R1 has at least one nitrogen atom. In some cases, the at least one nitrogen at of the heterocycle of R1 is bound to Formula (II*). In some cases, R1 is selected from an optionally substituted 10-membered spiro heterocycle and optionally substituted 10-membered fused heterocycle. In some cases, the optional one or more substituents of R1 are independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)OR20, -C(O)NHOR20, - N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkynyl, 5- to 12- membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, and C1-6 alkyl. In some cases, R1 is selected from
Figure imgf000136_0001
, which is substituted with one or more substituents independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, - C(=NR20)N(R20)2, -C(O)OR20, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6 alkyl- N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12- membered heterocycle is optionally substituted with one or more substituents selected from
Figure imgf000136_0002
Figure imgf000137_0001
Figure imgf000137_0002
some cases, M is selected from O. In some cases, M is NCH2CH3. In some cases, M is NMe. In some cases, the heterocycle of R2 is a saturated heterocycle. In some cases, R6 of R2 is independently selected at each occurrence from halogen, =CH2, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl. In some cases, L of R2 is selected from C1-C4 alkylene and . In some cases, R2 is selected from
Figure imgf000137_0003
,
Figure imgf000137_0004
some cases, B is selected from an optionally substituted C9-C10 fused carbocycle. In some cases, B is selected from
Figure imgf000137_0005
, each of which is optionally substituted. In some cases, B is optionally substituted with one or more substituents independently selected from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, -OH, -O-C1-C3 haloalkyl, -C(O)NH2, -NH2, =O, -CN, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl. In some cases, B is optionally substituted with one or more substituents independently selected from halogen. In some cases,
Figure imgf000138_0001
. some cases,
Figure imgf000138_0002
. some cases, B is unsubstituted. In some cases, B is substituted. [00375] In some embodiments, for a compound or salt of Formula (II*), R1 is selected from an optionally substituted 7- to 10-membered spiro heterocycle and optionally substituted 7- to 10- membered fused heterocycle. In some cases, R1 is selected from an optionally substituted 10- membered spiro heterocycle and optionally substituted 10-membered fused heterocycle. In some cases, R1 is selected from an optionally substituted 10-membered spiro heterocycle. In some cases, R1 is selected from an optionally substituted 10-membered fused heterocycle. In some cases, the heterocycle of R1 has at least 3 heteroatoms. In some cases, the optional one or more substituents of R1 are independently selected from halogen, -OH, -S(O)2(R20), -S(O)N(R20)2, - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)OR20, - C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, and C1-6 alkyl. In
Figure imgf000138_0003
some cases, R1 is selected from , which is substituted with one or more substituents independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)OR20, -C(O)NHOR20, -N(R20)2, - C(O)R20, -NO2, =O, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, and C1-6 alkyl. In some cases, R1 is selected from
Figure imgf000138_0004
,
Figure imgf000139_0001
Figure imgf000140_0001
cases, M is selected from O. In some cases, M is NMe. In some cases, the heterocycle of R2 is a saturated heterocycle. In some cases, R6 of R2 is independently selected at each occurrence from halogen, =CH2, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl. In some cases, L of R2 is selected from C1-C4 alkylene
Figure imgf000140_0002
.
Figure imgf000140_0003
is optionally substituted. In some cases, B is optionally substituted with one or more substituents independently selected from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, -OH, -O-C1-C3 haloalkyl, -C(O)NH2, -NH2, =O, -CN, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl. In some cases, B is optionally substituted with one or more substituents independently selected from halogen. In some cases,
Figure imgf000141_0001
. some cases,
Figure imgf000141_0002
. some cases, B is unsubstituted. In some cases, B is substituted. [00376] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), the heterocycle or carbocycle of R1 is not substituted by C1-6 cyanoalkyl. In some embodiments, for a compound or salt of Formula (I), the heterocycle or carbocycle of R1 is not substituted by C1-6 cyanoalkyl. In some embodiments, for a compound or salt of Formula (II), the heterocycle or carbocycle of R1 is not substituted by C1-6 cyanoalkyl. In some embodiments, for a compound or salt of Formula (III), the heterocycle or carbocycle of R1 is not substituted by C1-6 cyanoalkyl. [00377] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), each R20 is independently selected from hydrogen; and C1-6 alkyl. [00378] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), is not substituted by C1-6 cyanoalkyl. [00379] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 is not a piperazine. In some cases, R1 is not a substituted piperazine. [00380] In some embodiments, for a compound of Formula (I), wherein the compound is not a Michael acceptor. [00381] In some embodiments, for a compound of Formula (I), the compound or salt does not include an electrophilic substituent. [00382] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), does not contain an electrophile moiety. [00383] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), does not contain a covalent modifier. [00384] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), the one or more optional substituents of R1 are not electrophiles. [00385] In some embodiments, the compounds of Formula (I), (II), (II*), (III), or subformulas used in the methods include trifluoroacetic acid salts of the above compounds. [00386] In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 5 mg to about 500 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 150 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 125 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 25 mg to about 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the compound or salt of Formula (II) of is administered to a subject at about 5 mg to about 75 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg , about 30 mg, about 45 mg, or about 60 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 30 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 45 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 60 mg. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old. [00387] In some embodiments, a compound or salt of Formula (II) is administered once daily. In some embodiments, the compound or salt of Formula (II) is administered twice daily. In some embodiments, the compound or salt of Formula (II) is administered 3 times daily. In some embodiments, the compound or salt of Formula (II) is administered once weekly. In some embodiments, the compound or salt of Formula (II) is administered every other day. In some embodiments, the compound or salt of Formula (II) is administered every 3 days. [00388] In some embodiments, the compound or salt of Formula (II) is administered to a subject at 10 mg to 150 mg. In some embodiments, the compound or salt of Formula (II) or a salt thereof is administered to a subject at 10 mg to 125 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 10 mg to 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 25 mg to 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 50 mg to 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 5 mg to 75 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 15 mg, 30 mg, 45 mg, or 60 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 15 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 30 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 45 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 60 mg. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old. [00389] In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 150 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 125 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 25 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 50 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 5 mg to about 75 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 30 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 45 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 60 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered once daily. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old. [00390] In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 150 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 125 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 100 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 25 mg to about 100 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 50 mg to about 100 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 5 mg to about 75 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 30 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 45 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 60 mg, twice daily. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old. [00391] In some embodiments, a compound of Formula (II) is administered as a capsule during the period of time. In some cases, a tablet or capsule formulation of a compound of Formula (II) comprises about 10 mg to about 100 mg (e.g., about 10 mg to about 95 mg, about 10 mg to about 90 mg, about 10 mg to about 85 mg, about 10 mg to about 80 mg, about 10 mg to about 75 mg, about 10 mg to about 70 mg, about 10 mg to about 65 mg, about 10 mg to about 60 mg, about 10 mg to about 55 mg, about 10 mg to about 50 mg, about 10 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 15 mg to about 100 mg, about 15 mg to about 95 mg, about 15 mg to about 90 mg, about 15 mg to about 85 mg, about 15 mg to about 80 mg, about 15 mg to about 75 mg, about 15 mg to about 70 mg, about 15 mg to about 65 mg, about 15 mg to about 60 mg, about 15 mg to about 55 mg, about 15 mg to about 50 mg, about 15 mg to about 45 mg, about 15 mg to about 40 mg, about 15 mg to about 35 mg, about 15 mg to about 30 mg, about 15 mg to about 25 mg, about 15 mg to about 20 mg, about 20 mg to about 100 mg, about 20 mg to about 95 mg, about 20 mg to about 90 mg, about 20 mg to about 85 mg, about 20 mg to about 80 mg, about 20 mg to about 75 mg, about 20 mg to about 70 mg, about 20 mg to about 65 mg, about 20 mg to about 60 mg, about 20 mg to about 55 mg, about 20 mg to about 50 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, about 25 mg to about 100 mg, about 25 mg to about 95 mg, about 25 mg to about 90 mg, about 25 mg to about 85 mg, about 25 mg to about 80 mg, about 25 mg to about 75 mg, about 25 mg to about 70 mg, about 25 mg to about 65 mg, about 25 mg to about 60 mg, about 25 mg to about 55 mg, about 25 mg to about 50 mg, about 25 mg to about 45 mg, about 25 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 30 mg to about 100 mg, about 30 mg to about 95 mg, about 30 mg to about 90 mg, about 30 mg to about 85 mg, about 30 mg to about 80 mg, about 30 mg to about 75 mg, about 30 mg to about 70 mg, about 30 mg to about 65 mg, about 30 mg to about 60 mg, about 30 mg to about 55 mg, about 30 mg to about 50 mg, about 30 mg to about 45 mg, about 30 mg to about 40 mg, about 30 mg to about 35 mg, about 35 mg to about 100 mg, about 35 mg to about 95 mg, about 35 mg to about 90 mg, about 35 mg to about 85 mg, about 35 mg to about 80 mg, about 35 mg to about 75 mg, about 35 mg to about 70 mg, about 35 mg to about 65 mg, about 35 mg to about 60 mg, about 35 mg to about 55 mg, about 35 mg to about 50 mg, about 35 mg to about 45 mg, about 35 mg to about 40 mg, about 40 mg to about 100 mg, about 40 mg to about 95 mg, about 40 mg to about 90 mg, about 40 mg to about 85 mg, about 40 mg to about 80 mg, about 40 mg to about 75 mg, about 40 mg to about 70 mg, about 40 mg to about 65 mg, about 40 mg to about 60 mg, about 40 mg to about 55 mg, about 40 mg to about 50 mg, about 40 mg to about 45 mg, about 45 mg to about 100 mg, about 45 mg to about 95 mg, about 45 mg to about 90 mg, about 45 mg to about 85 mg, about 45 mg to about 80 mg, about 45 mg to about 75 mg, about 45 mg to about 70 mg, about 45 mg to about 65 mg, about 45 mg to about 60 mg, about 45 mg to about 55 mg, about 45 mg to about 50 mg, about 50 mg to about 100 mg, about 50 mg to about 95 mg, about 50 mg to about 90 mg, about 50 mg to about 85 mg, about 50 mg to about 80 mg, about 50 mg to about 75 mg, about 50 mg to about 70 mg, about 50 mg to about 65 mg, about 50 mg to about 60 mg, about 50 mg to about 55 mg, about 55 mg to about 100 mg, about 55 mg to about 95 mg, about 55 mg to about 90 mg, about 55 mg to about 85 mg, about 55 mg to about 80 mg, about 55 mg to about 75 mg, about 55 mg to about 70 mg, about 55 mg to about 65 mg, about 55 mg to about 60 mg, about 60 mg to about 100 mg, about 60 mg to about 95 mg, about 60 mg to about 90 mg, about 60 mg to about 85 mg, about 60 mg to about 80 mg, about 60 mg to about 75 mg, about 60 mg to about 70 mg, about 60 mg to about 65 mg, about 65 mg to about 100 mg, about 65 mg to about 95 mg, about 65 mg to about 90 mg, about 65 mg to about 85 mg, about 65 mg to about 80 mg, about 65 mg to about 75 mg, about 65 mg to about 70 mg, about 70 mg to about 100 mg, about 70 mg to about 95 mg, about 70 mg to about 90 mg, about 70 mg to about 85 mg, about 70 mg to about 80 mg, about 70 mg to about 75 mg, about 75 mg to about 100 mg, about 75 mg to about 95 mg, about 75 mg to about 90 mg, about 75 mg to about 85 mg, about 75 mg to about 80 mg, about 80 mg to about 100 mg, about 80 mg to about 95 mg, about 80 mg to about 90 mg, about 80 mg to about 85 mg, about 85 mg to about 100 mg, about 85 mg to about 95 mg, about 85 mg to about 90 mg, about 90 mg to about 100 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg) of a compound of Formula (II) (e.g., compound 53, 61, 63, 64, 69, and 96), or a pharmaceutically acceptable salt thereof. [00392] In some embodiments, a compound of Formula (II) is orally administered once a day (QD) on a daily basis during a period of time. In one embodiment, a compound of Formula (II) is orally administered twice a day (BID) on a daily basis during a period of time. In one embodiment, a compound of Formula (II) is orally administered in the amount of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 500 mg, about 40 mg to about 480 mg, about 40 mg to about 460 mg, about 40 mg to about 440 mg, about 40 mg to about 420 mg, about 40 mg to about 400 mg, about 40 mg to about 380 mg, about 40 mg to about 360 mg, about 40 mg to about 340 mg, about 40 mg to about 320 mg, about 40 mg to about 300 mg, about 40 mg to about 280 mg, about 40 mg to about 260 mg, about 40 mg to about 240 mg, about 40 mg to about 220 mg, about 40 mg to about 200 mg, about 40 mg to about 180 mg, about 40 mg to about 160 mg, about 40 mg to about 140 mg, about 40 mg to about 120 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 500 mg, about 60 mg to about 480 mg, about 60 mg to about 460 mg, about 60 mg to about 440 mg, about 60 mg to about 420 mg, about 60 mg to about 400 mg, about 60 mg to about 380 mg, about 60 mg to about 360 mg, about 60 mg to about 340 mg, about 60 mg to about 320 mg, about 60 mg to about 300 mg, about 60 mg to about 280 mg, about 60 mg to about 260 mg, about 60 mg to about 240 mg, about 60 mg to about 220 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg, about 80 mg to about 500 mg, about 80 mg to about 480 mg, about 80 mg to about 460 mg, about 80 mg to about 440 mg, about 80 mg to about 420 mg, about 80 mg to about 400 mg, about 80 mg to about 380 mg, about 80 mg to about 360 mg, about 80 mg to about 340 mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg, about 80 mg to about 280 mg, about 80 mg to about 260 mg, about 80 mg to about 240 mg, about 80 mg to about 220 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about 100 mg to about 500 mg, about 100 mg to about 480 mg, about 100 mg to about 460 mg, about 100 mg to about 440 mg, about 100 mg to about 420 mg, about 100 mg to about 400 mg, about 100 mg to about 380 mg, about 100 mg to about 360 mg, about 100 mg to about 340 mg, about 100 mg to about 320 mg, about 100 mg to about 300 mg, about 100 mg to about 280 mg, about 100 mg to about 260 mg, about 100 mg to about 240 mg, about 100 mg to about 220 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 500 mg, about 120 mg to about 480 mg, about 120 mg to about 460 mg, about 120 mg to about 440 mg, about 120 mg to about 420 mg, about 120 mg to about 400 mg, about 120 mg to about 380 mg, about 120 mg to about 360 mg, about 120 mg to about 340 mg, about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 500 mg, about 140 mg to about 480 mg, about 140 mg to about 460 mg, about 140 mg to about 440 mg, about 140 mg to about 420 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg to about 260 mg, about 140 mg to about 240 mg, about 140 mg to about 220 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mg, about 160 mg to about 500 mg, about 160 mg to about 480 mg, about 160 mg to about 460 mg, about 160 mg to about 440 mg, about 160 mg to about 420 mg, about 160 mg to about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 mg to about 220 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 500 mg, about 180 mg to about 480 mg, about 180 mg to about 460 mg, about 180 mg to about 440 mg, about 180 mg to about 420 mg, about 180 mg to about 400 mg, about 180 mg to about 380 mg, about 180 mg to about 360 mg, about 180 mg to about 340 mg, about 180 mg to about 320 mg, about 180 mg to about 300 mg, about 180 mg to about 280 mg, about 180 mg to about 260 mg, about 180 mg to about 240 mg, about 180 mg to about 220 mg, about 180 mg to about 200 mg, about 200 mg to about 500 mg, about 200 mg to about 480 mg, about 200 mg to about 460 mg, about 200 mg to about 440 mg, about 200 mg to about 420 mg, about 200 mg to about 400 mg, about 200 mg to about 380 mg, about 200 mg to about 360 mg, about 200 mg to about 340 mg, about 200 mg to about 320 mg, about 200 mg to about 300 mg, about 200 mg to about 280 mg, about 200 mg to about 260 mg, about 200 mg to about 240 mg, about 200 mg to about 220 mg, about 220 mg to about 500 mg, about 220 mg to about 480 mg, about 220 mg to about 460 mg, about 220 mg to about 440 mg, about 220 mg to about 420 mg, about 220 mg to about 400 mg, about 220 mg to about 380 mg, about 220 mg to about 360 mg, about 220 mg to about 340 mg, about 220 mg to about 320 mg, about 220 mg to about 300 mg, about 220 mg to about 280 mg, about 220 mg to about 260 mg, about 220 mg to about 240 mg, about 240 mg to about 500 mg, about 240 mg to about 480 mg, about 240 mg to about 460 mg, about 240 mg to about 440 mg, about 240 mg to about 420 mg, about 240 mg to about 400 mg, about 240 mg to about 380 mg, about 240 mg to about 360 mg, about 240 mg to about 340 mg, about 240 mg to about 320 mg, about 240 mg to about 300 mg, about 240 mg to about 280 mg, about 240 mg to about 260 mg, about 260 mg to about 500 mg, about 260 mg to about 480 mg, about 260 mg to about 460 mg, about 260 mg to about 440 mg, about 260 mg to about 420 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about 340 mg, about 260 mg to about 320 mg, about 260 mg to about 300 mg, about 260 mg to about 280 mg, about 280 mg to about 500 mg, about 280 mg to about 480 mg, about 280 mg to about 460 mg, about 280 mg to about 440 mg, about 280 mg to about 420 mg, about 280 mg to about 400 mg, about 280 mg to about 380 mg, about 280 mg to about 360 mg, about 280 mg to about 340 mg, about 280 mg to about 320 mg, about 280 mg to about 300 mg, about 300 mg to about 500 mg, about 300 mg to about 480 mg, about 300 mg to about 460 mg, about 300 mg to about 440 mg, about 300 mg to about 420 mg, about 300 mg to about 400 mg, about 300 mg to about 380 mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 500 mg, about 320 mg to about 480 mg, about 320 mg to about 460 mg, about 320 mg to about 440 mg, about 320 mg to about 420 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 320 mg to about 340 mg, about 340 mg to about 500 mg, about 340 mg to about 480 mg, about 340 mg to about 460 mg, about 340 mg to about 440 mg, about 340 mg to about 420 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 500 mg, about 360 mg to about 480 mg, about 360 mg to about 460 mg, about 360 mg to about 440 mg, about 360 mg to about 420 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 500 mg, about 380 mg to about 480 mg, about 380 mg to about 460 mg, about 380 mg to about 440 mg, about 380 mg to about 420 mg, about 380 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 480 mg, about 400 mg to about 460 mg, about 400 mg to about 440 mg, about 400 mg to about 420 mg, about 420 mg to about 500 mg, about 420 mg to about 480 mg, about 420 mg to about 460 mg, about 420 mg to about 440 mg, about 440 mg to about 500 mg, about 440 mg to about 480 mg, about 440 mg to about 460 mg, about 460 mg to about 500 mg, about 460 mg to about 480 mg, about 480 mg to about 500 mg, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 mg), during a period of time. [00393] In some embodiments, the combination therapy comprises oral administration of a compound of Formula (II) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg (e.g., about 10 mg to about 380 mg, about 10 mg to about 360 mg, about 10 mg to about 340 mg, about 10 mg to about 320 mg, about 10 mg to about 300 mg, about 10 mg to about 280 mg, about 10 mg to about 260 mg, about 10 mg to about 240 mg, about 10 mg to about 220 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 140 mg, about 10 mg to about 120 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 40 mg, about 10 mg to about 20 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 400 mg, about 40 mg to about 380 mg, about 40 mg to about 360 mg, about 40 mg to about 340 mg, about 40 mg to about 320 mg, about 40 mg to about 300 mg, about 40 mg to about 280 mg, about 40 mg to about 260 mg, about 40 mg to about 240 mg, about 40 mg to about 220 mg, about 40 mg to about 200 mg, about 40 mg to about 180 mg, about 40 mg to about 160 mg, about 40 mg to about 140 mg, about 40 mg to about 120 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 400 mg, about 60 mg to about 380 mg, about 60 mg to about 360 mg, about 60 mg to about 340 mg, about 60 mg to about 320 mg, about 60 mg to about 300 mg, about 60 mg to about 280 mg, about 60 mg to about 260 mg, about 60 mg to about 240 mg, about 60 mg to about 220 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg, about 80 mg to about 400 mg, about 80 mg to about 380 mg, about 80 mg to about 360 mg, about 80 mg to about 340 mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg, about 80 mg to about 280 mg, about 80 mg to about 260 mg, about 80 mg to about 240 mg, about 80 mg to about 220 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about 100 mg to about 400 mg, about 100 mg to about 380 mg, about 100 mg to about 360 mg, about 100 mg to about 340 mg, about 100 mg to about 320 mg, about 100 mg to about 300 mg, about 100 mg to about 280 mg, about 100 mg to about 260 mg, about 100 mg to about 240 mg, about 100 mg to about 220 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 400 mg, about 120 mg to about 380 mg, about 120 mg to about 360 mg, about 120 mg to about 340 mg, about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg to about 260 mg, about 140 mg to about 240 mg, about 140 mg to about 220 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mg, about 160 mg to about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 360 mg, about 160 mg to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 mg to about 220 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 400 mg, about 180 mg to about 380 mg, about 180 mg to about 360 mg, about 180 mg to about 340 mg, about 180 mg to about 320 mg, about 180 mg to about 300 mg, about 180 mg to about 280 mg, about 180 mg to about 260 mg, about 180 mg to about 240 mg, about 180 mg to about 220 mg, about 180 mg to about 200 mg, about 200 mg to about 400 mg, about 200 mg to about 380 mg, about 200 mg to about 360 mg, about 200 mg to about 340 mg, about 200 mg to about 320 mg, about 200 mg to about 300 mg, about 200 mg to about 280 mg, about 200 mg to about 260 mg, about 200 mg to about 240 mg, about 200 mg to about 220 mg, about 220 mg to about 400 mg, about 220 mg to about 380 mg, about 220 mg to about 360 mg, about 220 mg to about 340 mg, about 220 mg to about 320 mg, about 220 mg to about 300 mg, about 220 mg to about 280 mg, about 220 mg to about 260 mg, about 220 mg to about 240 mg, about 240 mg to about 400 mg, about 240 mg to about 380 mg, about 240 mg to about 360 mg, about 240 mg to about 340 mg, about 240 mg to about 320 mg, about 240 mg to about 300 mg, about 240 mg to about 280 mg, about 240 mg to about 260 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about 340 mg, about 260 mg to about 320 mg, about 260 mg to about 300 mg, about 260 mg to about 280 mg, about 280 mg to about 400 mg, about 280 mg to about 380 mg, about 280 mg to about 360 mg, about 280 mg to about 340 mg, about 280 mg to about 320 mg, about 280 mg to about 300 mg, about 300 mg to about 400 mg, about 300 mg to about 380 mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 340 mg to about 360 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 400 mg, about 100 mg, about 200 mg, about 300 mg, or about 400 mg), and oral administration of an inhibitor selected from: 1) immunomodulator inhibitor; 2) PD-1 inhibitor; 3) PD-L1 inhibitor; and 4) CTLA-4 inhibitor; or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time). In some cases, the inhibitor is an immunomodulator inhibitor. In some cases, the inhibitor is an PD-1 inhibitor. In some cases, the inhibitor is an PD-L1 inhibitor. In some cases, the inhibitor is an CTLA-4 inhibitor. In some cases, the compound of Formula (II) is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is selected compound 53, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 61 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 63 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 64 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 69 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 96, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is orally administered once daily. In one embodiment, the compound of Formula (II) is orally administered twice daily. [00394] In some embodiments, a compound of Formula (II), or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered as a tablet or capsule. In one embodiment, a tablet or capsule formulation of a compound of Formula (II) comprises about 10 mg to about 100 mg (e.g., about 10 mg to about 95 mg, about 10 mg to about 90 mg, about 10 mg to about 85 mg, about 10 mg to about 80 mg, about 10 mg to about 75 mg, about 10 mg to about 70 mg, about 10 mg to about 65 mg, about 10 mg to about 60 mg, about 10 mg to about 55 mg, about 10 mg to about 50 mg, about 10 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 15 mg to about 100 mg, about 15 mg to about 95 mg, about 15 mg to about 90 mg, about 15 mg to about 85 mg, about 15 mg to about 80 mg, about 15 mg to about 75 mg, about 15 mg to about 70 mg, about 15 mg to about 65 mg, about 15 mg to about 60 mg, about 15 mg to about 55 mg, about 15 mg to about 50 mg, about 15 mg to about 45 mg, about 15 mg to about 40 mg, about 15 mg to about 35 mg, about 15 mg to about 30 mg, about 15 mg to about 25 mg, about 15 mg to about 20 mg, about 20 mg to about 100 mg, about 20 mg to about 95 mg, about 20 mg to about 90 mg, about 20 mg to about 85 mg, about 20 mg to about 80 mg, about 20 mg to about 75 mg, about 20 mg to about 70 mg, about 20 mg to about 65 mg, about 20 mg to about 60 mg, about 20 mg to about 55 mg, about 20 mg to about 50 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, about 25 mg to about 100 mg, about 25 mg to about 95 mg, about 25 mg to about 90 mg, about 25 mg to about 85 mg, about 25 mg to about 80 mg, about 25 mg to about 75 mg, about 25 mg to about 70 mg, about 25 mg to about 65 mg, about 25 mg to about 60 mg, about 25 mg to about 55 mg, about 25 mg to about 50 mg, about 25 mg to about 45 mg, about 25 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 30 mg to about 100 mg, about 30 mg to about 95 mg, about 30 mg to about 90 mg, about 30 mg to about 85 mg, about 30 mg to about 80 mg, about 30 mg to about 75 mg, about 30 mg to about 70 mg, about 30 mg to about 65 mg, about 30 mg to about 60 mg, about 30 mg to about 55 mg, about 30 mg to about 50 mg, about 30 mg to about 45 mg, about 30 mg to about 40 mg, about 30 mg to about 35 mg, about 35 mg to about 100 mg, about 35 mg to about 95 mg, about 35 mg to about 90 mg, about 35 mg to about 85 mg, about 35 mg to about 80 mg, about 35 mg to about 75 mg, about 35 mg to about 70 mg, about 35 mg to about 65 mg, about 35 mg to about 60 mg, about 35 mg to about 55 mg, about 35 mg to about 50 mg, about 35 mg to about 45 mg, about 35 mg to about 40 mg, about 40 mg to about 100 mg, about 40 mg to about 95 mg, about 40 mg to about 90 mg, about 40 mg to about 85 mg, about 40 mg to about 80 mg, about 40 mg to about 75 mg, about 40 mg to about 70 mg, about 40 mg to about 65 mg, about 40 mg to about 60 mg, about 40 mg to about 55 mg, about 40 mg to about 50 mg, about 40 mg to about 45 mg, about 45 mg to about 100 mg, about 45 mg to about 95 mg, about 45 mg to about 90 mg, about 45 mg to about 85 mg, about 45 mg to about 80 mg, about 45 mg to about 75 mg, about 45 mg to about 70 mg, about 45 mg to about 65 mg, about 45 mg to about 60 mg, about 45 mg to about 55 mg, about 45 mg to about 50 mg, about 50 mg to about 100 mg, about 50 mg to about 95 mg, about 50 mg to about 90 mg, about 50 mg to about 85 mg, about 50 mg to about 80 mg, about 50 mg to about 75 mg, about 50 mg to about 70 mg, about 50 mg to about 65 mg, about 50 mg to about 60 mg, about 50 mg to about 55 mg, about 55 mg to about 100 mg, about 55 mg to about 95 mg, about 55 mg to about 90 mg, about 55 mg to about 85 mg, about 55 mg to about 80 mg, about 55 mg to about 75 mg, about 55 mg to about 70 mg, about 55 mg to about 65 mg, about 55 mg to about 60 mg, about 60 mg to about 100 mg, about 60 mg to about 95 mg, about 60 mg to about 90 mg, about 60 mg to about 85 mg, about 60 mg to about 80 mg, about 60 mg to about 75 mg, about 60 mg to about 70 mg, about 60 mg to about 65 mg, about 65 mg to about 100 mg, about 65 mg to about 95 mg, about 65 mg to about 90 mg, about 65 mg to about 85 mg, about 65 mg to about 80 mg, about 65 mg to about 75 mg, about 65 mg to about 70 mg, about 70 mg to about 100 mg, about 70 mg to about 95 mg, about 70 mg to about 90 mg, about 70 mg to about 85 mg, about 70 mg to about 80 mg, about 70 mg to about 75 mg, about 75 mg to about 100 mg, about 75 mg to about 95 mg, about 75 mg to about 90 mg, about 75 mg to about 85 mg, about 75 mg to about 80 mg, about 80 mg to about 100 mg, about 80 mg to about 95 mg, about 80 mg to about 90 mg, about 80 mg to about 85 mg, about 85 mg to about 100 mg, about 85 mg to about 95 mg, about 85 mg to about 90 mg, about 90 mg to about 100 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg. In some cases, a compound is selected form In some embodiments, a compound of Formula (II) is orally administered once a day (QD) on a daily basis during a period of time. In some embodiments, a compound of Formula (II) is orally administered twice a day (BID) on a daily basis during a period of time. In one embodiment, a compound of Formula (II) is orally administered in the amount of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 500 mg, about 40 mg to about 480 mg, about 40 mg to about 460 mg, about 40 mg to about 440 mg, about 40 mg to about 420 mg, about 40 mg to about 400 mg, about 40 mg to about 380 mg, about 40 mg to about 360 mg, about 40 mg to about 340 mg, about 40 mg to about 320 mg, about 40 mg to about 300 mg, about 40 mg to about 280 mg, about 40 mg to about 260 mg, about 40 mg to about 240 mg, about 40 mg to about 220 mg, about 40 mg to about 200 mg, about 40 mg to about 180 mg, about 40 mg to about 160 mg, about 40 mg to about 140 mg, about 40 mg to about 120 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 500 mg, about 60 mg to about 480 mg, about 60 mg to about 460 mg, about 60 mg to about 440 mg, about 60 mg to about 420 mg, about 60 mg to about 400 mg, about 60 mg to about 380 mg, about 60 mg to about 360 mg, about 60 mg to about 340 mg, about 60 mg to about 320 mg, about 60 mg to about 300 mg, about 60 mg to about 280 mg, about 60 mg to about 260 mg, about 60 mg to about 240 mg, about 60 mg to about 220 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg, about 80 mg to about 500 mg, about 80 mg to about 480 mg, about 80 mg to about 460 mg, about 80 mg to about 440 mg, about 80 mg to about 420 mg, about 80 mg to about 400 mg, about 80 mg to about 380 mg, about 80 mg to about 360 mg, about 80 mg to about 340 mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg, about 80 mg to about 280 mg, about 80 mg to about 260 mg, about 80 mg to about 240 mg, about 80 mg to about 220 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about 100 mg to about 500 mg, about 100 mg to about 480 mg, about 100 mg to about 460 mg, about 100 mg to about 440 mg, about 100 mg to about 420 mg, about 100 mg to about 400 mg, about 100 mg to about 380 mg, about 100 mg to about 360 mg, about 100 mg to about 340 mg, about 100 mg to about 320 mg, about 100 mg to about 300 mg, about 100 mg to about 280 mg, about 100 mg to about 260 mg, about 100 mg to about 240 mg, about 100 mg to about 220 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 500 mg, about 120 mg to about 480 mg, about 120 mg to about 460 mg, about 120 mg to about 440 mg, about 120 mg to about 420 mg, about 120 mg to about 400 mg, about 120 mg to about 380 mg, about 120 mg to about 360 mg, about 120 mg to about 340 mg, about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 500 mg, about 140 mg to about 480 mg, about 140 mg to about 460 mg, about 140 mg to about 440 mg, about 140 mg to about 420 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg to about 260 mg, about 140 mg to about 240 mg, about 140 mg to about 220 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mg, about 160 mg to about 500 mg, about 160 mg to about 480 mg, about 160 mg to about 460 mg, about 160 mg to about 440 mg, about 160 mg to about 420 mg, about 160 mg to about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 mg to about 220 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 500 mg, about 180 mg to about 480 mg, about 180 mg to about 460 mg, about 180 mg to about 440 mg, about 180 mg to about 420 mg, about 180 mg to about 400 mg, about 180 mg to about 380 mg, about 180 mg to about 360 mg, about 180 mg to about 340 mg, about 180 mg to about 320 mg, about 180 mg to about 300 mg, about 180 mg to about 280 mg, about 180 mg to about 260 mg, about 180 mg to about 240 mg, about 180 mg to about 220 mg, about 180 mg to about 200 mg, about 200 mg to about 500 mg, about 200 mg to about 480 mg, about 200 mg to about 460 mg, about 200 mg to about 440 mg, about 200 mg to about 420 mg, about 200 mg to about 400 mg, about 200 mg to about 380 mg, about 200 mg to about 360 mg, about 200 mg to about 340 mg, about 200 mg to about 320 mg, about 200 mg to about 300 mg, about 200 mg to about 280 mg, about 200 mg to about 260 mg, about 200 mg to about 240 mg, about 200 mg to about 220 mg, about 220 mg to about 500 mg, about 220 mg to about 480 mg, about 220 mg to about 460 mg, about 220 mg to about 440 mg, about 220 mg to about 420 mg, about 220 mg to about 400 mg, about 220 mg to about 380 mg, about 220 mg to about 360 mg, about 220 mg to about 340 mg, about 220 mg to about 320 mg, about 220 mg to about 300 mg, about 220 mg to about 280 mg, about 220 mg to about 260 mg, about 220 mg to about 240 mg, about 240 mg to about 500 mg, about 240 mg to about 480 mg, about 240 mg to about 460 mg, about 240 mg to about 440 mg, about 240 mg to about 420 mg, about 240 mg to about 400 mg, about 240 mg to about 380 mg, about 240 mg to about 360 mg, about 240 mg to about 340 mg, about 240 mg to about 320 mg, about 240 mg to about 300 mg, about 240 mg to about 280 mg, about 240 mg to about 260 mg, about 260 mg to about 500 mg, about 260 mg to about 480 mg, about 260 mg to about 460 mg, about 260 mg to about 440 mg, about 260 mg to about 420 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about 340 mg, about 260 mg to about 320 mg, about 260 mg to about 300 mg, about 260 mg to about 280 mg, about 280 mg to about 500 mg, about 280 mg to about 480 mg, about 280 mg to about 460 mg, about 280 mg to about 440 mg, about 280 mg to about 420 mg, about 280 mg to about 400 mg, about 280 mg to about 380 mg, about 280 mg to about 360 mg, about 280 mg to about 340 mg, about 280 mg to about 320 mg, about 280 mg to about 300 mg, about 300 mg to about 500 mg, about 300 mg to about 480 mg, about 300 mg to about 460 mg, about 300 mg to about 440 mg, about 300 mg to about 420 mg, about 300 mg to about 400 mg, about 300 mg to about 380 mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 500 mg, about 320 mg to about 480 mg, about 320 mg to about 460 mg, about 320 mg to about 440 mg, about 320 mg to about 420 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 320 mg to about 340 mg, about 340 mg to about 500 mg, about 340 mg to about 480 mg, about 340 mg to about 460 mg, about 340 mg to about 440 mg, about 340 mg to about 420 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 500 mg, about 360 mg to about 480 mg, about 360 mg to about 460 mg, about 360 mg to about 440 mg, about 360 mg to about 420 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 500 mg, about 380 mg to about 480 mg, about 380 mg to about 460 mg, about 380 mg to about 440 mg, about 380 mg to about 420 mg, about 380 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 480 mg, about 400 mg to about 460 mg, about 400 mg to about 440 mg, about 400 mg to about 420 mg, about 420 mg to about 500 mg, about 420 mg to about 480 mg, about 420 mg to about 460 mg, about 420 mg to about 440 mg, about 440 mg to about 500 mg, about 440 mg to about 480 mg, about 440 mg to about 460 mg, about 460 mg to about 500 mg, about 460 mg to about 480 mg, about 480 mg to about 500 mg, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 mg), during a period of time, and i.v. administration of an inhibitor, wherein the inhibitor is selected from: 1) immunomodulator inhibitor; 2) PD-1 inhibitor; 3) PD-L1 inhibitor; and 4) CTLA-4 inhibitor; wherein the inhibitor is administered, for example, once a week, once every two weeks, once every three weeks, or once every four weeks, depending on the dosage. In some cases, the compound of Formula (II) is selected compound 53, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 61 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 63 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 64 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 69 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 96, or a pharmaceutically acceptable salt of any one thereof. [00395] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein. The compounds of the present invention that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide. [00396] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well. [00397] A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:
Figure imgf000158_0001
. [00398] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, 11C, 13C and/or 14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs. [00399] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of the present disclosure. [00400] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with 2H, 11C, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 16O, 17O, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35Cl, 37Cl, 79Br, 81Br, and 125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. [00401] In certain embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with 2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods. [00402] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32. [00403] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co. [00404] Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. [00405] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. [00406] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. [00407] In certain embodiments, compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure. [00408] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound. [00409] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell. [00410] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials. [00411] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995). Pharmaceutical Formulations [00412] Provided herein, in certain embodiments, are compositions comprising a therapeutically effective amount of a compound of Formulas (I), (II), (II*), (III), an immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor, or a pharmaceutically acceptable salt of any one thereof (also referred to herein as “a pharmaceutical agent”). [00413] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999). [00414] The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the pharmaceutical agent, is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration, e.g., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier, the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop. [00415] A pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self emulsifying drug delivery system or a self microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer. [00416] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, or as an eye drop. The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. [00417] A pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion. The excipients described herein are examples and are in no way limiting. An effective amount or therapeutically effective amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect. [00418] Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein. Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and/or in the urine, and/or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course. [00419] The dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts. In addition to the factors described herein and above related to use of pharmaceutical agent for treating a disease or disorder, suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration. Optimal doses of an agent may generally be determined using experimental models and/or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre- clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy. In certain particular embodiments, two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone. An amount of a pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg/kg and 100 mg/kg, e.g., between about 0.1 to 1 mg/kg, between about 1 to 10 mg/kg, between about 10-50 mg/kg, between about 50-100 mg/kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg/kg and 1000 mg/kg, between about 100-500 mg/kg, or between about 500-1000 mg/kg body weight. The optimal dose, per day or per course of treatment, may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen. [00420] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art. The composition may be in the form of a solid, e.g., tablet, capsule, semi-solid, e.g., gel, liquid, or gas, e.g., aerosol. In other embodiments, the pharmaceutical composition is administered as a bolus infusion. [00421] Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. In general, the type of excipient is selected based on the mode of administration, as well as the chemical composition of the active ingredient(s). Alternatively, compositions described herein may be formulated as a lyophilizate. A composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and/or diluting the pharmaceutical agent(s) of the composition upon administration. In other embodiments, the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art. In certain particular embodiments, a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries. Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art. [00422] A pharmaceutical composition, e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may be in the form of a liquid. A liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile. In another embodiment, for treatment of an ophthalmological condition or disease, a liquid pharmaceutical composition may be applied to the eye in the form of eye drops. A liquid pharmaceutical composition may be delivered orally. [00423] For oral formulations, at least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents. The pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and/or an enteric coating. A pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and/or with an enteric coating. [00424] A pharmaceutical composition comprising any one of the pharmaceutical agents described herein may be formulated for sustained or slow release, also called timed release or controlled release. Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain the compound dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release. The amount of pharmaceutical agent contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition, disease or disorder to be treated or prevented. [00425] In certain embodiments, the pharmaceutical compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration. The compositions can be administered using a syringe, bandage, transdermal patch, insert, or syringe- like applicator, as a powder/talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste. This preferably is in the form of a controlled release formulation or sustained release formulation administered topically or injected directly into the skin adjacent to or within the area to be treated, e.g., intradermally or subcutaneously. The active compositions can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof. [00426] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated as emulsions for topical application. An emulsion contains one liquid distributed in the body of a second liquid. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. The oil phase may contain other oily pharmaceutically approved excipients. Suitable surfactants include, but are not limited to, anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant. [00427] Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Liquid sprays may be delivered from pressurized packs, for example, via a specially shaped closure. Oil-in-water emulsions can also be used in the compositions, patches, bandages and articles. These systems are semisolid emulsions, micro-emulsions, or foam emulsion systems. [00428] In some embodiments, the pharmaceutical agent described herein can be formulated as in inhalant. Inhaled methods can deliver medication directly to the airway. The pharmaceutical agent can be formulated as aerosols, microspheres, liposomes, or nanoparticles. The pharmaceutical agent can be formulated with solvents, gases, nitrates, or any combinations thereof. Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles. Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue. [00429] Aerosolized formulations described herein are optionally delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having with a mass medium average diameter predominantly between 1 to 5 ^. Further, the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the pharmaceutical agent. Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects. [00430] Aerosolization devices suitable for administration of aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-5 ^. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 ^ range. A jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNeb ^ ^ and AeroDose ^ ^ ^vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream ^ nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC ^ and Pari LC Star ^ jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and Aerosonic ^ ^ (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire ^ (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers. [00431] In some embodiments, the pharmaceutical agent(s) can be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape. In addition to the pharmaceutical agent, these semisolid compositions can contain dissolved and/or suspended bactericidal agents, preservatives and/or a buffer system. A petrolatum component that may be included may be any paraffin ranging in viscosity from mineral oil that incorporates isobutylene, colloidal silica, or stearate salts to paraffin waxes. Absorption bases can be used with an oleaginous system. Additives may include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination. [00432] Controlled or sustained release transdermal or topical formulations can be achieved by the addition of time-release additives, such as polymeric structures, matrices, that are available in the art. For example, the compositions may be administered through use of hot-melt extrusion articles, such as bioadhesive hot-melt extruded film. The formulation can comprise a cross- linked polycarboxylic acid polymer formulation. A cross-linking agent may be present in an amount that provides adequate adhesion to allow the system to remain attached to target epithelial or endothelial cell surfaces for a sufficient time to allow the desired release of the compound. [00433] An insert, transdermal patch, bandage or article can comprise a mixture or coating of polymers that provide release of the pharmaceutical agents at a constant rate over a prolonged period of time. In some embodiments, the article, transdermal patch or insert comprises water- soluble pore forming agents, such as polyethylene glycol (PEG) that can be mixed with water insoluble polymers to increase the durability of the insert and to prolong the release of the active ingredients. [00434] Transdermal devices (inserts, patches, bandages) may also comprise a water insoluble polymer. Rate controlling polymers may be useful for administration to sites where pH change can be used to effect release. These rate controlling polymers can be applied using a continuous coating film during the process of spraying and drying with the active compound. In one embodiment, the coating formulation is used to coat pellets comprising the active ingredients that are compressed to form a solid, biodegradable insert. [00435] A polymer formulation can also be utilized to provide controlled or sustained release. Bioadhesive polymers described in the art may be used. By way of example, a sustained-release gel and the compound may be incorporated in a polymeric matrix, such as a hydrophobic polymer matrix. Examples of a polymeric matrix include a microparticle. The microparticles can be microspheres, and the core may be of a different material than the polymeric shell. Alternatively, the polymer may be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel. The polymer can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent. The matrices can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art. [00436] Kits with unit doses of one or more of the agents described herein, usually in oral or injectable doses, are provided. Such kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating disease, and optionally an appliance or device for delivery of the composition. KITS AND PRODUCTS Immunomodulator inhibitor combination Kit [00437] Some embodiments relate to kits and products that include the compound or salt of Formula (II) and/or an immunomodulator inhibitor. For example, the kit or product can include a package or container with a compound of Formula (II) or pharmaceutically acceptable salt. Such kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound or salt of Formula (II) in combination with an immunomodulator inhibitor that is separately provided. The kits can be used in the methods of treating cancer as described herein. [00438] In some embodiments, the kits or products can include both a compound or salt of Formula (II) and an immunomodulator inhibitor. [00439] Such kits can include one or more containers or packages, which include one or both combination drugs together in a single container and/or package, or in separate packages/containers. In some instances, the two drugs are separately wrapped, but included in a single package, container or box. Such kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound or salt of Formula (II) in combination with an immunomodulator inhibitor. The kits can be used in the methods of treating cancer as described herein. [00440] In some embodiments, the compound or salt of Formula (II) is selected from compounds 53, 61, 63, 64, 69, and 96. PD-1 inhibitor combination Kit [00441] Some embodiments relate to kits and products that include the compound or salt of Formula (II) and/or at least one PD-1 inhibitor. For example, the kit or product can include a package or container with a compound or salt of Formula (II). Such kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound or salt of Formula (II) in combination with an PD-1 inhibitor that is separately provided. The kits can be used in the methods of treating cancer as described herein. [00442] In some embodiments, the kits or products can include both a compound of Formula (II) and at least one PD-1 inhibitor. [00443] Such kits can include one or more containers or packages, which include one or both combination drugs together in a single container and/or package, or in separate packages/containers. In some instances, the two drugs are separately wrapped, but included in a single package, container or box. Such kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound or salt of Formula (II) in combination with an PD-1 inhibitor. The kits can be used in the methods of treating cancer as described herein. [00444] In some embodiments, the compound or salt of Formula (II) is selected from compounds 53, 61, 63, 64, 69, and 96. PD-L1 inhibitor combination Kit [00445] Some embodiments relate to kits and products that include the compound of Formula (II) and/or at least one PD-L1 inhibitor. For example, the kit or product can include a package or container with a compound or salt of Formula (II). Such kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound or salt of Formula (II) in combination with an PD-L1 inhibitor that is separately provided. The kits can be used in the methods of treating cancer as described herein. [00446] In some embodiments, the kits or products can include both a compound of Formula (II) and at least one PD-L1 inhibitor. [00447] Such kits can include one or more containers or packages, which include one or both combination drugs together in a single container and/or package, or in separate packages/containers. In some instances, the two drugs are separately wrapped, but included in a single package, container or box. Such kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound or salt of Formula (II) in combination with an PD-L1 inhibitor. The kits can be used in the methods of treating cancer as described herein. [00448] In some embodiments, the compound or salt of Formula (II) is selected from compounds 53, 61, 63, 64, 69, and 96. CTLA-4 inhibitor combination Kit [00449] Some embodiments relate to kits and products that include the compound of Formula (II) and/or at least one CTLA-4 inhibitor. For example, the kit or product can include a package or container with a compound of Formula (II). Such kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound of Formula (II) in combination with an CTLA-4 inhibitor that is separately provided. The kits can be used in the methods of treating cancer as described herein. [00450] In some embodiments, the kits or products can include both a compound or salt of Formula (II) and at least one CTLA-4 inhibitor. [00451] Such kits can include one or more containers or packages, which include one or both combination drugs together in a single container and/or package, or in separate packages/containers. In some instances, the two drugs are separately wrapped, but included in a single package, container or box. Such kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound of Formula (II) in combination with an CTLA-4 inhibitor. The kits can be used in the methods of treating cancer as described herein. [00452] In some embodiments, the compound or salt of Formula (II) is selected from compounds 53, 61, 63, 64, 69, and 96. DOSINGS [00453] In some embodiments, the dosage regimen for the compounds herein (e.g, an immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor; or a compound or salt of Formula (II), or a pharmaceutical composition of any one thereof) will vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. In some embodiments, a clinical practitioner can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the disease or disorder. In some cases, depending on the patient’s condition and the intended therapeutic effect, the dosing frequency for the therapeutic agent may vary, for example, from once per day to six times per day. That is, the dosing frequency may be QD, i.e., once per day, BID, i.e., twice per day; TID, i.e., three times per day; QID, i.e., four times per day; five times per day, or six times per day. In another embodiment, dosing frequency may be BIW, i.e., twice weekly, TIW, i.e., three times a week, or QIW, i.e. four times a week. In some cases, depending on the patient’s condition and the intended therapeutic effect, the treatment cycle may have a period of time where no therapeutic agent is administered. As used herein, “interval administration” refers to administration of the therapeutic agent (e.g, an immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor; or a compound or salt of Formula (II)) followed by void days or void weeks. For example, the treatment cycle may be 3 weeks long which includes 2 weeks of dosing of the therapeutic agent(s) followed by 1 week where no therapeutic agent is administered. In some embodiments, the treatment cycle is 4 weeks long which includes 3 weeks of dosing followed by 1 week where no therapeutic agent is administered. [00454] In some embodiments, the daily oral dosage of each active ingredient (e.g, immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor; or a compound or salt of Formula (II)), when used for the indicated effects, will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about l00 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day. In some embodiments, an active ingredient (e.g, an immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor; or a compound or salt of Formula (II)), may be administered at a dose of between about 10 mg/day and about 200 mg/day. In some embodiments, an active ingredient (e.g, an immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor; or a compound or salt of Formula (II)), may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day. The dose may be any value or subrange within the recited ranges. [00455] The term “treatment cycle” as used herein, means a pre-determined period of time for administering the therapeutic agent (e.g, an immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor; or a compound or salt of Formula (II)). In some embodiments, the patient is examined at the end of each treatment cycle to evaluate the effect of the therapy. In some cases, each of the treatment cycle has about 3 or more days. In some cases, each of the treatment cycle has from about 3 days to about 60 days. In some cases, each of the treatment cycle has from about 5 days to about 50 days. In some cases, each of the treatment cycle has from about 7 days to about 28 days. In some cases, each of the treatment cycle has 28 days. In some cases, the treatment cycle has about 29 days. In some cases, the treatment cycle has about 30 days. In some cases, the treatment cycle has about 31 days. In some cases, the treatment cycle has about a month-long treatment cycle. In some cases, the treatment cycle is any length of time from 3 weeks to 8 weeks. In some cases, the treatment cycle is any length of time from 3 weeks to 6 weeks. In some cases, the treatment cycle is 3 weeks. In some cases, the treatment cycle is one month. In some cases, the treatment cycle is 4 weeks. In some cases, the treatment cycle is 5 weeks. In some cases, the treatment cycle is 6 weeks. In some cases, the treatment cycle is 7 weeks. In some cases, the treatment cycle is 8 weeks. In some cases, the duration of the treatment cycle may include any value or subrange within the recited ranges, including endpoints. [00456] In some embodiments, drugs are administered at the maximum tolerated dose (“MTD”), which is the highest dose of drug that does not cause unacceptable side effects. Immunomodulator inhibitor Dosing [00457] In some embodiments, the immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof is administered prior to administration of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof. [00458] In some embodiments, the immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, is administered after administration of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof. [00459] In some embodiments, the immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, is administered at about the same time as administration of the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof. In some embodiments, separate administration of each inhibitor/compound, at different times and by different routes, may be advantageous. In some cases, the components in the combination i.e. compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, and the immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, need not be necessarily administered at essentially the same time or in any order. [00460] In some embodiments, a pharmaceutical composition comprises an immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some cases, a pharmaceutical composition comprises a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some cases, the pharmaceutical compositions may be used in the methods simultaneously, separately, or sequentially. In some cases, a pharmaceutical composition comprises an immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, and/or a compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, for use in the methods for simultaneous, separate or sequential use. [00461] In some cases, the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are each dosed at their respective MTDs. In some cases, the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD and the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed in an amount less than its MTD. In some cases, the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at an amount less than its MTD and the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD. In some cases, the compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at less than their respective MTDs. In some cases, the administration can be so timed that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other. [00462] In some embodiments, the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is administered QD. In some cases, the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are administered BID. In some cases, the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID. [00463] In some embodiments, a single dose of compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each administered once daily. [00464] In some embodiments, the therapeutically effective amount of the immunomodulator inhibitor of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day. In some embodiments, the therapeutically effective amount of the immunomodulator inhibitor of the combination will range between about 10 mg/day and about 200 mg/day. In some embodiments, the therapeutically effective amount of the immunomodulator inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day. The therapeutically effective amount of the immunomodulator inhibitor of the combination may be any value or subrange within the recited ranges. [00465] In some embodiments, the therapeutically effective amount of the immunomodulator inhibitor of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day. In some embodiments, the therapeutically effective amount of the immunomodulator inhibitor of the combination will range between about 0.1 to about 50 mg/kg of body weight. In some embodiments the therapeutically effective amount of the immunomodulator inhibitor of the combination will range between about 10 mg/day and about 200 mg/day. In some embodiments, the therapeutically effective amount of the immunomodulator inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day. The therapeutically effective amount of the immunomodulator inhibitor of the combination may be any value or subrange within the recited ranges. [00466] In some embodiments, the immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, and the compound of Formula (II), or a pharmaceutically acceptable salt thereof, can be formulated into separate or individual dosage forms which can be co- administered one after the other. In some embodiments, if the route of administration is the same (e.g. oral) two active compounds can be formulated into a single form for co-administration, both methods of co-administration, however, being part of the same therapeutic treatment or regimen. In some embodiments, the combination therapy comprises oral administration of a compound of Formula (II) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg and oral administration of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time). In some embodiments, the combination therapy comprises oral administration of a compound of Formula (II) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg and oral administration of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time). In some embodiments, the combination therapy comprises oral administration of a compound of Formula (II) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg and oral administration of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time). [00467] In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 5 mg to about 600 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 10 mg to about 150 mg. In some embodiments, the immunomodulator inhibitor is administered to a subject at about 10 mg to about 125 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 440 mg to about 520 mg. In some embodiments, the immunomodulator inhibitor is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the immunomodulator inhibitor is administered to a subject at about 25 mg to about 100 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof of is administered to a subject at about 5 mg to about 75 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 170 mg, about 190 mg, about 210 mg, about 240 mg, about 300 mg, about 350 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 540 mg, about 580 mg, or about 650 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg , about 30 mg, about 45 mg, or about 60 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 30 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 45 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 60 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 240 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 480 mg. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old. [00468] In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered once daily. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered twice daily. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered 3 times daily. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered once weekly. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered every other day. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered every 3 days. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered once a week. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered every two weeks. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered every 4 weeks. [00469] In some embodiments, the immunomodulator inhibitor is administered intravenously in the amount of about 800 mg every 2 weeks (Q2W) or about 10 mg/kg every 2 weeks (Q2W). In one embodiment, the immunomodulator inhibitor, is administered intravenously over 60 minutes. [00470] In some embodiments, the immunomodulator inhibitor, is administered at a dose of 1200 mg intravenously once every 3 weeks (Q3W) or at a dose of 840 mg intravenously two weeks apart. In some cases, the immunomodulator inhibitor, is administered intravenously over 60 minutes. [00471] In some embodiments, the immunomodulator inhibitor, is administered at a dose of 10 mg/kg intravenously once every 2 weeks (Q2W). In one embodiment, the immunomodulator inhibitor, is administered intravenously over 60 minutes. PD-1 inhibitor Dosing [00472] In some embodiments, a pharmaceutical composition comprises a PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some cases, a pharmaceutical composition comprises a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some cases, the pharmaceutical compositions may be used in the methods simultaneously, separately, or sequentially. [00473] In some embodiments, a pharmaceutical composition comprises a PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, and/or a compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, for use in the methods which may be for simultaneous, separate or sequential use. [00474] In some cases, the PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered prior to administration of the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another embodiment, the PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered after administration of the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another embodiment, the PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered at about the same time as administration of the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some embodiments, separate administration of each inhibitor, at different times and by different routes, may be advantageous. In some cases, the components in the combination i.e. compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and the PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, may need not to be administered at essentially the same time or in any order. [00475] In some embodiments, the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are each dosed at their respective MTDs. In some cases, the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD and the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed in an amount less than its MTD. In some cases, the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at an amount less than its MTD and the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD. In some cases, the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at less than their respective MTDs. In some cases, the administration can be so timed that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other. [00476] In some embodiments, the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is administered QD. In some cases, the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are administered BID. In some cases, the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID. [00477] In some embodiments, a single dose of compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each administered once daily. [00478] In some embodiments, the therapeutically effective amount of the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof) of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day. In some embodiments, a PD-1 inhibitor the therapeutically effective amount of the PD-1 inhibitor of the combination will range between about 10 mg/day and about 200 mg/day. In some embodiments, the therapeutically effective amount of the PD-1 inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day. The therapeutically effective amount of the PD-1 inhibitor of the combination may be any value or subrange within the recited ranges. [00479] In some embodiments, the therapeutically effective amount of the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof) of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day. In some embodiments, the therapeutically effective amount of the PD-1 inhibitor of the combination will range between about 0.1 to about 50 mg/kg of body weight. In some embodiments, the therapeutically effective amount of the PD-1 inhibitor of the combination will range between about 10 mg/day and about 200 mg/day. In some embodiments, the therapeutically effective amount of the PD-1 inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day. The therapeutically effective amount of the PD-1 inhibitor of the combination may be any value or subrange within the recited ranges. [00480] In some embodiments, the therapeutically effective amount of the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof) of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per time, and most preferably between about 0.1 to about 20 mg/kg/time. In some embodiments, the therapeutically effective amount of the PD-1 inhibitor of the combination will range between about 0.1 to about 50 mg/kg of body weight. In some embodiments, the therapeutically effective amount of the PD-1 inhibitor of the combination will range between about 10 mg/time and about 200 mg/time. In some embodiments, the therapeutically effective amount of the PD-1 inhibitor of the combination may be administered at a dose of about 10 mg/time, 20 mg/time, 30 mg/time, 40 mg/time, 50 mg/time, 60 mg/time, 70 mg/time, 80 mg/time, 90 mg/time, 100 mg/time, 110 mg/time, 120 mg/time, 130 mg/time, 140 mg/time, 150 mg/time, 160 mg/time, 170 mg/time, 180 mg/time, 190 mg/time, 200 mg/time, 240 mg/time, 480 mg/time, 600 mg/time 1000 mg/time. The therapeutically effective amount of the PD-1 inhibitor of the combination may be any value or subrange within the recited ranges. In some cases, the time is 1 day. In some cases, the time is 7 days. In some cases, the time is 14 days. In some cases, the time is 21 days. In some cases, the time is 28 days. [00481] In some embodiments, the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), or a pharmaceutically acceptable salt thereof, and the compound of Formula (II), or a pharmaceutically acceptable salt thereof, can be formulated into separate or individual dosage forms which can be co-administered one after the other. In some cases, if the route of administration is the same (e.g. oral) two active compounds can be formulated into a single form for co-administration, both methods of co-administration, however, being part of the same therapeutic treatment or regimen. In some embodiments, the combination therapy comprises oral administration of a compound of Formula (II) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg and oral administration of a PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time). [00482] In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 5 mg to about 600 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 10 mg to about 150 mg. In some embodiments, the PD-1 inhibitor is administered to a subject at about 10 mg to about 125 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 440 mg to about 520 mg. In some embodiments the PD-1 inhibitor is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the PD-1 inhibitor is administered to a subject at about 25 mg to about 100 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof of is administered to a subject at about 5 mg to about 75 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 170 mg, about 190 mg, about 210 mg, about 240 mg, about 300 mg, about 350 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 540 mg, about 580 mg, or about 650 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg , about 30 mg, about 45 mg, or about 60 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 30 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 45 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 60 mg. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old. [00483] In some embodiments, the PD-1 inhibitor(e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), or pharmaceutically salt thereof is administered once daily. In some embodiments, the PD-1 inhibitor(e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), is administered twice daily. In some embodiments, the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), or pharmaceutically salt thereof is administered 3 times daily. In some embodiments, the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), is administered once weekly. In some embodiments, the the PD-1 inhibitor(e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), is administered every other day. In some embodiments, the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), is administered every 3 days. In some embodiments, the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), is administered once a week. In some embodiments, the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), is administered every two weeks. In some embodiments, the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), is administered every 4 weeks. [00484] In some embodiments, the PD-1 inhibitor is nivolumab or a biosimilar thereof. In one embodiment, nivolumab or a biosimilar thereof is administered at a dose of 240 mg intravenously once every 2 weeks (Q2W). In one embodiment, nivolumab or a biosimilar thereof is administered at a dose of 480 mg intravenously once every 4 weeks (Q4W). In one embodiment, nivolumab or a biosimilar thereof is administered intravenously over 30 minutes. [00485] In some embodiments, the PD-1 inhibitor is pembrolizumab or a biosimilar thereof. In one embodiment, pembrolizumab is administered at a dose of 200 mg intravenously once every 3 weeks (Q3W). In one embodiment, pembrolizumab or a biosimilar thereof is administered intravenously over 60 minutes. [00486] In some embodiments, the PD-1 inhibitor is cemiplimab or a biosimilar thereof. In one embodiment, cemiplimab or a biosimilar thereof is administered at a dose of 350 mg intravenously once every 3 weeks (Q3W). In one embodiment, cemiplimab or a biosimilar thereof is administered intravenously over 30 minutes. [00487] In some embodiments, the PD-1 inhibitor is tislelizumab or a biosimilar thereof. In one embodiment, tislelizumab or a biosimilar thereof is administered at a dose of 200 mg intravenously once every 3 weeks (Q3W). [00488] In some embodiments, the therapeutically effective amount of pembrolizumab or biosimilar thereof in the combination is about 350 mg administered every three weeks. [00489] In some embodiments, the PD-1 inhibitor is tislelizumab or a biosimilar thereof. In some embodiments, the therapeutically effective amount of tislelizumab, or biosimilar thereof, in the combination is about 200 mg administered every three weeks. [00490] In some embodiments, the PD-1 inhibitor is atezolizumab or a biosimilar thereof. In some cases, the therapeutically effective amount of atezolizumab or biosimilar thereof in the combination is about 1200 mg administered every three weeks. [00491] In some embodiments, the PD-1 inhibitor is the PD-L1 inhibitor is avelumab or a biosimilar thereof. In some cases, the therapeutically effective amount of avelumab or biosimilar thereof in the combination is about 10 mg/kg administered every two weeks or 800 mg every two weeks. [00492] In some embodiments, the PD-L1 inhibitor is durvalumab or a biosimilar thereof. In some cases, the therapeutically effective amount of durvalumab or biosimilar thereof in the combination is about 10 mg/kg administered every two weeks. PD-L1 inhibitor Dosing [00493] In some embodiments, a pharmaceutical compositions comprise a PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some cases, a pharmaceutical composition comprises a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some cases, the pharmaceutical compositions may be used in the methods simultaneously, separately, or sequentially. [00494] In some embodiments, the pharmaceutical compositions comprise a PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), or a pharmaceutically acceptable salt thereof, and/or a compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, for use in the methods may be for simultaneous, separate or sequential use. In some cases, the PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered prior to administration of the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another embodiment, the PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered after administration of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another embodiment, the PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered at about the same time as administration of the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, separate administration of each inhibitor, at different times and by different routes, may be advantageous. Thus, the components in the combination i.e. compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and the PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, may need not be necessarily administered at essentially the same time or in any order. In some cases, the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are each dosed at their respective MTDs. In some cases, the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD and the PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed in an amount less than its MTD. In some cases, the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at an amount less than its MTD and the PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD. In some cases, the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at less than their respective MTDs. In some cases, the administration can be so timed that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other. [00495] In some embodiments, the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is administered QD. In some cases, the PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are administered BID. In some cases, the PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID. In some embodiments, a single dose of compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each administered once daily. [00496] In some embodiments, the therapeutically effective amount of the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof) of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day. In some embodiments, a PD-L1 inhibitor the therapeutically effective amount of the PD-L1 inhibitor of the combination will range between about 10 mg/day and about 200 mg/day. In some embodiments, the therapeutically effective amount of the PD-L1 inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day. The therapeutically effective amount of the PD-L1 inhibitor of the combination may be any value or subrange within the recited ranges. [00497] In some embodiments, the therapeutically effective amount of the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof) of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per time, and most preferably between about 0.1 to about 20 mg/kg/time. In some embodiments, the therapeutically effective amount of the PD-L1 inhibitor of the combination will range between about 0.1 to about 50 mg/kg of body weight. In some embodiments, the therapeutically effective amount of the PD-L1 inhibitor of the combination will range between about 10 mg/time and about 200 mg/time. In some embodiments, the therapeutically effective amount of the PD-L1 inhibitor of the combination may be administered at a dose of about 10 mg/time, 20 mg/time, 30 mg/time, 40 mg/time, 50 mg/time, 60 mg/time, 70 mg/time, 80 mg/time, 90 mg/time, 100 mg/time, 110 mg/time, 120 mg/time, 130 mg/time, 140 mg/time, 150 mg/time, 160 mg/time, 170 mg/time, 180 mg/time, 190 mg/time, 200 mg/time, 240 mg/time, 300 mg/time, 480 mg/time. The therapeutically effective amount of the PD-L1 inhibitor of the combination may be any value or subrange within the recited ranges. In some cases, the time is 1 day. In some cases, the time is 7 days. In some cases, the time is 14 days. In some cases, the time is 21 days. In some cases, the time is 28 days. [00498] In some embodiments, the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), or a pharmaceutically acceptable salt thereof, and the compound of Formula (II), or a pharmaceutically acceptable salt thereof, can be formulated into separate or individual dosage forms which can be co-administered one after the other. Another option is that if the route of administration is the same (e.g. oral) two active compounds can be formulated into a single form for co-administration, both methods of co-administration, however, being part of the same therapeutic treatment or regimen. In some embodiments, the combination therapy comprises oral administration of a compound of Formula (II) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg and oral administration of a PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time). [00499] In some embodiments, the PD-L1 inhibitor is administered to a subject at about 200 mg to about 500 mg. In some embodiments, PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 440 mg to about 520 mg. In some embodiments PD-L1 inhibitor is administered to a subject at about 10 mg to about 100 mg. In some embodiments, PD-L1 inhibitor is administered to a subject at about 240 mg to about 480 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof of is administered to a subject at about 5 mg to about 75 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 170 mg, about 190 mg, about 210 mg, about 240 mg, about 300 mg, about 350 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 540 mg, about 580 mg, or about 650 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg , about 30 mg, about 45 mg, or about 60 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 30 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 240 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 480 mg. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old. [00500] In some embodiments, the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), or pharmaceutically salt thereof is administered once daily. In some embodiments, the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), is administered twice daily. In some embodiments, the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), or pharmaceutically salt thereof is administered 3 times daily. In some embodiments, the PD-L1 inhibitor(e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), is administered once weekly. In some embodiments, the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), is administered every other day. In some embodiments, the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), is administered every 3 days. In some embodiments, the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), is administered once a week. In some embodiments, the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), is administered every two weeks. In some embodiments, the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), is administered every 4 weeks. [00501] In some embodiments, the PD-L1 inhibitor is avelumab or a biosimilar thereof. In one embodiment, avelumab or a biosimilar thereof is administered intravenously in the amount of about 800 mg every 2 weeks (Q2W) or about 10 mg/kg every 2 weeks (Q2W). In one embodiment, avelumab or a biosimilar thereof is administered intravenously over 60 minutes. [00502] In some embodiments, the PD-L1 inhibitor is atezolizumab or a biosimilar thereof. In some cases, atezolizumab or a biosimilar thereof is administered at a dose of 1200 mg intravenously once every 3 weeks (Q3W) or at a dose of 840 mg intravenously two weeks apart. In some cases, atezolizumab or a biosimilar thereof is administered intravenously over 60 minutes. [00503] In some embodiments, the PD-L1 inhibitor is durvalumab or a biosimilar thereof. In one embodiment, durvalumab or a biosimilar thereof is administered at a dose of 10 mg/kg intravenously once every 2 weeks (Q2W). In one embodiment, durvalumab or a biosimilar thereof is administered intravenously over 60 minutes. CTLA-4 inhibitor Dosing [00504] In some embodiments, a pharmaceutical composition comprises a CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some cases, a pharmaceutical composition comprises a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some cases, the pharmaceutical compositions may be used in the methods simultaneously, separately, or sequentially. [00505] In some embodiments, the pharmaceutical compositions comprising a CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, and/or a compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, for use in the methods may be for simultaneous, separate or sequential use. [00506] In some embodiments, the CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered prior to administration of the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another embodiment, the CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered after administration of the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another embodiment, the CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered at about the same time as administration of the compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, separate administration of each inhibitor, at different times and by different routes, may be advantageous. In some cases, the components in the combination i.e. compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof and the CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, need not be necessarily administered at essentially the same time or in any order. In some cases, the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are each dosed at their respective MTDs. In some cases, the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD and the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed in an amount less than its MTD. In some cases, the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at an amount less than its MTD and the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD. In some cases, the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at less than their respective MTDs. In some cases, the administration can be so timed that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other. [00507] In some embodiments, the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is administered QD. In some cases, the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are administered BID. In some cases, the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID. [00508] In some embodiments, a single dose of compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each administered once daily. [00509] In some embodiments, the therapeutically effective amount of the CTLA-4 inhibitor of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day. In some embodiments, the therapeutically effective amount of the CTLA-4 inhibitor of the combination will range between about 10 mg/day and about 200 mg/day. In some cases, the therapeutically effective amount of the CTLA-4 inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day. The therapeutically effective amount of the CTLA-4 inhibitor of the combination may be any value or subrange within the recited ranges. [00510] In some embodiments, the therapeutically effective amount of the CTLA-4 inhibitor of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day. In some embodiments, the therapeutically effective amount of the CTLA-4 inhibitor of the combination will range between about 0.1 to about 50 mg/kg of body weight. In some embodiments, the therapeutically effective amount of the CTLA- 4 inhibitor of the combination will range between about 10 mg/day and about 200 mg/day. In some embodiments, the therapeutically effective amount of the CTLA-4 inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day. The therapeutically effective amount of the CTLA-4 inhibitor of the combination may be any value or subrange within the recited ranges. [00511] In some embodiments, the CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, and the compound of Formula (II), or a pharmaceutically acceptable salt thereof, can be formulated into separate or individual dosage forms which can be co-administered one after the other. In some cases, if the route of administration is the same (e.g. oral) two active compounds can be formulated into a single form for co-administration, both methods of co-administration, however, being part of the same therapeutic treatment or regimen. In some embodiments, the combination therapy comprises oral administration of a compound of Formula (II) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg and oral administration of a CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time). [00512] In some embodiments, the CTLA-4 inhibitor is administered to a subject at about 200 mg to about 500 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 440 mg to about 520 mg. In some embodiments, the CTLA-4 inhibitor is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the CTLA-4 inhibitor is administered to a subject at about 240 mg to about 480 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof of is administered to a subject at about 5 mg to about 75 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 170 mg, about 190 mg, about 210 mg, about 240 mg, about 300 mg, about 350 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 540 mg, about 580 mg, or about 650 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg , about 30 mg, about 45 mg, or about 60 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 30 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 240 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 480 mg. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old. [00513] In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered once daily. In some embodiments, the CTLA-4 inhibitor, is administered twice daily. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered 3 times daily. In some embodiments, the CTLA-4 inhibitor, is administered once weekly. In some embodiments, the CTLA-4 inhibitor, is administered every other day. In some embodiments, the CTLA-4 inhibitor, is administered every 3 days. In some embodiments, the CTLA-4 inhibitor, is administered once a week. In some embodiments, the CTLA-4 inhibitor, is administered every two weeks. In some embodiments, the CTLA-4 inhibitor, is administered every 4 weeks. KRAS Inhibitor Dosing [00514] In some embodiments, a single dose of compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is administered per day (i.e., in about 24 hour intervals) (i.e., QD). In some cases, two doses of the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are administered per day (i.e., BID). In some cases, three doses of the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are administered per day (i.e., TID). COMBINATION THERAPIES Immunomodulator inhibitor combination therapy [00515] In an aspect the present disclosure provides methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. [00516] In an aspect the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. In one embodiment, the cancer is a KRas G12D-associated cancer. In one embodiment, the cancer is a KRas G12V-associated cancer. In one embodiment, the cancer is a KRas wildtype-associated cancer. In some cases, the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer. In some cases, the cancer is a solid tumor cancer. In some cases, the cancer is a solid tumor cancer with a KRAS mutation. In some cases, the cancer is a solid tumor cancer with KRAS wildtype. In some cases, the cancer is a solid tumor cancer with a G12D mutation. In some cases, the cancer is a solid tumor cancer with a G12V mutation. In some cases, the cancer is a KRAS wildtype-associated cancer. In some cases, the KRas G12D-associated cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer. In some cases, the compound of Formula (II) is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof. In some cases, the compound of Formula (II) is compound 53. In some cases, the compound of Formula (II) is compound 61. In some cases, the compound of Formula (II) is compound 63. In some cases, the compound of Formula (II) is compound 64. In some cases, the compound of Formula (II) is compound 69. In some cases, the compound of Formula (II) is compound 96. [00517] In an aspect the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (II) selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. In some cases, the compound of Formula (II) is compound 53. In some cases, the compound of Formula (II) is compound 61. In some cases, the compound of Formula (II) is compound 63. In some cases, the compound of Formula (II) is compound 64. In some cases, the compound of Formula (II) is compound 69. In some cases, the compound of Formula (II) is compound 96. [00518] In an aspect the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a combination of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (II) selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. In some cases, the compound of Formula (II) is compound 53. In some cases, the compound of Formula (II) is compound 61. In some cases, the compound of Formula (II) is compound 63. In some cases, the compound of Formula (II) is compound 64. In some cases, the compound of Formula (II) is compound 69. In some cases, the compound of Formula (II) is compound 96. [00519] In an aspect the present disclosure provides methods for increasing the sensitivity of a cancer cell to a compound or salt of Formula (II), comprising contacting the cancer cell with an effective amount of a combination of a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the immunomodulator inhibitor synergistically increases the sensitivity of the cancer cell to the compound or salt of Formula (II). In some cases, the contacting is in vitro. In one embodiment, the contacting is in vivo. [00520] In an aspect the present disclosure provides methods of inhibiting KRas G12 mutants or wildtype in a subject comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. In some cases, the method may inhibit KRas G12 mutants or wildtype activity in a cell. In some cases, inhibiting KRas G12 mutants or wildtype activity in a cell may include contacting the cell in which inhibition of KRas G12 mutants or wildtype activity is desired with an effective amount of a compound of Formula (II), or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof and an immunomodulator inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. [00521] In some cases, a cell in which inhibition of KRas G12 mutants or wildtype activity is desired is contacted with an effective amount of a compound of Formula (II) or pharmaceutically acceptable salt of any one thereof and an immunomodulator inhibitor to negatively modulate the activity of KRas G12 mutants or wildtype. In some cases, by negatively modulating the activity of KRas G12 mutants or wildtype, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12 mutants or wildtype activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12 mutants or wildtype. The ability of compounds to bind KRas G12 mutants or wildtype may be monitored in vitro using well known methods. [00522] In some embodiments, the inhibitory activity of compounds of Formula (II) and an immunomodulator inhibitor in cells may be monitored, for example, by measuring the inhibition of KRas G12 mutants or wildtype activity of the amount of phosphorylated ERK. [00523] In an aspect the present disclosure provides methods of reprogramming a tumor microenvironment (TME) of a subject in favor of antitumor immunity, wherein reprogramming includes modulating tumor cell cytokine/chemokine release in the tumor microenvironment of the subject. The method includes providing a compound described herein (a compound of Formula (II), e.g., a compound selected from compounds 53, 61, 63, 64, 69, and 96). The method also includes providing an immunomodulator (e.g., checkpoint inhibitors (inhibitors targeting: cytotoxic T lymphocyte associated antigen 4 (CTLA-4), e.g. Yervoy/lpilimumab; programmed death 1/programmed death-ligand 1 (PD-1/PD-L1), e.g. Keytruda/pembrolizumab; and lymphocyte-activation gene 3 (LAG-3), e.g. BMS-986016/relatlimab)). The method can also include providing a compound of Formula (II) and an immunomodulator in combination (sequentially or simultaneously). In some cases, the subject has a KRas-associated cancer. [00524] In an aspect the present disclosure provides methods of treating a KRas G12D- associated cancer in a subject in need thereof, comprising administering to the subject a combination of an immunomodulator, and a compound of Formula (II) or a pharmaceutically acceptable salt thereof. In some cases, Formula (II) is Formula (II*). In some cases, the compound is selected from compounds 53, 61, 63, 64, 69, and 96. [00525] In an aspect the present disclosure provides methods of treating a KRas G12V- associated cancer in a subject in need thereof, comprising administering to the subject a combination of an immunomodulator, and a compound of Formula (II) or a pharmaceutically acceptable salt thereof. In some cases, Formula (II) is Formula (II*). In some cases, the compound is selected from compounds 53, 61, 63, 64, 69, and 96. [00526] In another aspect, methods of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound or salt of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided and an immunomodulator inhibitor. [00527] The compositions and methods provided herein may be used for the treatment of a KRas G12 mutants or wildtype-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (II), a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and an immunomodulator inhibitor are provided. In some cases, the KRas G12 mutants or wildtype associated cancer is lung cancer. In some cases, the KRas G12 mutants or wildtype associated cancer is solid tumor cancer. In some cases, the KRs G12 mutants are selected from G12D and G12V. In some cases, the KRas G12 mutants is G12D. In some cases, the KRas G12 mutants is G12V. [00528] In some embodiments, the method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a immunomodulator inhibitor and a compound or salt of Formula (II), synergistically increases the potency of the compound or salt of Formula (II). In some cases, the synergistic increase in potency of the compound or salt of Formula (II) results in an improved efficacy of the compound or salt of Formula (II). PD-1 inhibitor combination therapy [00529] In an aspect the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. In some cases, the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer. In some cases, the cancer is a solid tumor cancer. In some cases, the cancer is a solid tumor cancer with a KRAS mutation. In some cases, the cancer is a KRas wildtype-associated cancer. In one embodiment, the cancer is a KRas G12D-associated cancer. In one embodiment, the cancer is a KRas G12V-associated cancer. In one embodiment, the cancer is a KRas wildtype-associated cancer. In some cases, the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer. In some cases, the cancer is a solid tumor cancer. In some cases, the cancer is a solid tumor cancer with a KRas mutation. In some cases, the cancer is a solid tumor cancer with KRas wildtype. In some cases, the cancer is a solid tumor cancer with a G12D mutation. In some cases, the cancer is a solid tumor cancer with a G12V mutation. In some cases, the cancer is a KRas wildtype-associated cancer. In some cases, the KRas G12D-associated cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer. In some cases, the compound of Formula (II) is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof. In some cases, the compound of Formula (II) is compound 53. In some cases, the compound of Formula (II) is compound 61. In some cases, the compound of Formula (II) is compound 63. In some cases, the compound of Formula (II) is compound 64. In some cases, the compound of Formula (II) is compound 69. In some cases, the compound of Formula (II) is compound 96. [00530] In an aspect the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (II) selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. In some cases, the compound of Formula (II) is compound 53. In some cases, the compound of Formula (II) is compound 61. In some cases, the compound of Formula (II) is compound 63. In some cases, the compound of Formula (II) is compound 64. In some cases, the compound of Formula (II) is compound 69. In some cases, the compound of Formula (II) is compound 96. [00531] In an aspect the present disclosure provides methods for increasing the sensitivity of a cancer cell to a compound or salt of Formula (II), comprising contacting the cancer cell with an effective amount of a combination of a compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the PD-1 inhibitor synergistically increases the sensitivity of the cancer cell to the compound or salt of Formula (II). In some cases, the contacting is in vitro. In one embodiment, the contacting is in vivo. [00532] In an aspect the present disclosure provides methods of inhibiting KRas G12 mutants in a subject comprising administering to the subject a therapeutically effective amount of a combination of a PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (II),or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. In some cases, the method may inhibit KRas G12 mutants or wildtype activity in a cell. In some cases, inhibiting KRas G12 mutants or wildtype activity in a cell may include contacting the cell in which inhibition of KRas G12 mutants or wildtype activity is desired with an effective amount of a compound of Formula (II), or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt of any one thereof and a PD-1 inhibitor. In some cases, the contacting is in vitro. In some cases, the contacting is in vivo. In some cases, a cell in which inhibition of KRas G12 mutants or wildtype activity is desired is contacted with an effective amount of a compound of Formula (II), or pharmaceutically acceptable salt of any one thereof and a PD-1 inhibitor to negatively modulate the activity of KRas G12 mutants or wildtype. In some cases, by negatively modulating the activity of KRas G12 mutants or wildtype, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12 mutants or wildtype activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12 mutants or wildtype. The ability of compounds to bind KRas G12 mutants or wildtype may be monitored in vitro using well known methods. [00533] In some embodiments, the inhibitory activity of exemplary compounds and a PD-1 inhibitor in cells may be monitored, for example, by measuring the inhibition of KRas G12 mutants or wildtype activity of the amount of phosphorylated ERK. [00534] In another aspect, methods of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound or salt of Formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided and a PD-1 inhibitor. [00535] The compositions and methods provided herein may be used for the treatment of a KRas G12 mutants or wildtype -associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (II), a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a PD-1 inhibitor are provided. In some cases, the KRas G12 mutants or wildtype associated cancer is lung cancer. [00536] The compositions and methods provided herein may be used for the treatment of a KRas G12D-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (II), a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a PD-1 inhibitor are provided. [00537] In some embodiments, the method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a PD-1 inhibitor and a compound or salt of Formula (II), synergistically increases the potency of the compound or salt of Formula (II). In some cases, the synergistic increase in potency of the compound or salt of Formula (II) results in an improved efficacy of the compound or salt of Formula (II). PD-L1 inhibitor combination therapy [00538] In an aspect the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. In some cases, the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer. In some cases, the cancer is a solid tumor cancer. In some cases, the cancer is a solid tumor cancer with a KRas mutation. In some cases, the cancer is a KRAS wildtype-associated cancer. In one embodiment, the cancer is a KRas G12D-associated cancer. In one embodiment, the cancer is a KRas G12V-associated cancer. In one embodiment, the cancer is a KRas wildtype-associated cancer. In some cases, the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer. In some cases, the cancer is a solid tumor cancer. In some cases, the cancer is a solid tumor cancer with a KRAS mutation. In some cases, the cancer is a solid tumor cancer with KRAS wildtype. In some cases, the cancer is a solid tumor cancer with a G12D mutation. In some cases, the cancer is a solid tumor cancer with a G12V mutation. In some cases, the cancer is a KRAS wildtype-associated cancer. In some cases, the KRas G12D-associated cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer. In some cases, the compound of Formula (II) is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof. In some cases, the compound of Formula (II) is compound 53. In some cases, the compound of Formula (II) is compound 61. In some cases, the compound of Formula (II) is compound 63. In some cases, the compound of Formula (II) is compound 64. In some cases, the compound of Formula (II) is compound 69. In some cases, the compound of Formula (II) is compound 96. [00539] In an aspect the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (II) selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. In some cases, the compound of Formula (II) is compound 53. In some cases, the compound of Formula (II) is compound 61. In some cases, the compound of Formula (II) is compound 63. In some cases, the compound of Formula (II) is compound 64. In some cases, the compound of Formula (II) is compound 69. In some cases, the compound of Formula (II) is compound 96. [00540] In an aspect the present disclosure provides methods for increasing the sensitivity of a cancer cell to a compound or salt of Formula (II), comprising contacting the cancer cell with an effective amount of a combination of a compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the PD-L1 inhibitor synergistically increases the sensitivity of the cancer cell to the compound or salt of Formula (II). In some cases, the contacting is in vitro. In one embodiment, the contacting is in vivo. [00541] In an aspect the present disclosure provides methods of inhibiting KRas G12 mutants or wildtype in a subject comprising administering to the subject a therapeutically effective amount of a combination of a PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (II),or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. In some cases, the method may inhibit KRas G12 mutants or wildtype activity in a cell. In some cases, inhibiting KRas G12 mutants or wildtype activity in a cell may include contacting the cell in which inhibition of KRas G12 mutants or wildtype activity is desired with an effective amount of a compound of Formula (II), or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt of any one thereof and a PD-L1 inhibitor. In some cases, the contacting is in vitro. In some cases, the contacting is in vivo. In some cases, a cell in which inhibition of KRas G12 mutants or wildtype activity is desired is contacted with an effective amount of a compound of Formula (II) or pharmaceutically acceptable salt of any one thereof and an PD-L1 inhibitor to negatively modulate the activity of KRas G12 mutants or wildtype.. In some cases, by negatively modulating the activity of KRas G12 mutants or wildtype, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12 mutants or wildtype activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12 mutants or wildtype. The ability of compounds to bind KRas G12 mutants or wildtype may be monitored in vitro using well known methods. [00542] In some embodiments, the inhibitory activity of exemplary compounds and an PD-L1 inhibitor in cells may be monitored, for example, by measuring the inhibition of KRAS G12 mutants and wildtype activity of the amount of phosphorylated ERK. [00543] In another aspect, methods of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound or salt of Formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided and an PD-L1 inhibitor. [00544] The compositions and methods provided herein may be used for the treatment of a KRas G12 mutants or wildtype-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (II), a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a PD-L1 inhibitor are provided. In some cases, the KRas G12 mutants or wildtype associated cancer is lung cancer. [00545] In some embodiments, the method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a PD-L1 inhibitor and a compound or salt of Formula (II), synergistically increases the potency of the compound or salt of Formula (II). In some cases, the synergistic increase in potency of the compound or salt of Formula (II) results in an improved efficacy of the compound or salt of Formula (II). CTLA-4 inhibitor combination therapy [00546] In an aspect the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. In some cases, the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer. In some cases, the cancer is a solid tumor cancer. In some cases, the cancer is a solid tumor cancer with a KRAS mutation. In some cases, the cancer is a KRAS wildtype-associated cancer. In one embodiment, the cancer is a KRas G12D- associated cancer. In one embodiment, the cancer is a KRas G12V-associated cancer. In one embodiment, the cancer is a KRas wildtype-associated cancer. In some cases, the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer. In some cases, the cancer is a solid tumor cancer. In some cases, the cancer is a solid tumor cancer with a KRAS mutation. In some cases, the cancer is a solid tumor cancer with KRAS wildtype. In some cases, the cancer is a solid tumor cancer with a G12D mutation. In some cases, the cancer is a solid tumor cancer with a G12V mutation. In some cases, the cancer is a KRAS wildtype-associated cancer. In some cases, the KRas G12D-associated cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer. In some cases, the compound of Formula (II) is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof. In some cases, the compound of Formula (II) is compound 53. In some cases, the compound of Formula (II) is compound 61. In some cases, the compound of Formula (II) is compound 63. In some cases, the compound of Formula (II) is compound 64. In some cases, the compound of Formula (II) is compound 69. In some cases, the compound of Formula (II) is compound 96. [00547] In an aspect the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (II) selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. In some cases, the compound of Formula (II) is compound 53. In some cases, the compound of Formula (II) is compound 61. In some cases, the compound of Formula (II) is compound 63. In some cases, the compound of Formula (II) is compound 64. In some cases, the compound of Formula (II) is compound 69. In some cases, the compound of Formula (II) is compound 96. [00548] In an aspect the present disclosure provides methods for increasing the sensitivity of a cancer cell to a compound or salt of Formula (II), comprising contacting the cancer cell with an effective amount of a combination of a compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the CTLA-4 inhibitor synergistically increases the sensitivity of the cancer cell to the compound or salt of Formula (II). In some cases, the contacting is in vitro. In one embodiment, the contacting is in vivo. [00549] In an aspect the present disclosure provides methods of inhibiting KRas G12 mutants or wildtype in a subject comprising administering to the subject a therapeutically effective amount of a combination of a CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. In some cases, the method may inhibit KRas G12 mutants or wildtype activity in a cell. In some cases, inhibiting KRas G12 mutants or wildtype activity in a cell may include contacting the cell in which inhibition of KRas G12 mutants activity is desired with an effective amount of a compound of Formula (II), or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt of any one thereof and a CTLA-4 inhibitor. In some cases, the contacting is in vitro. In some cases, the contacting is in vivo. In some cases, a cell in which inhibition of KRas G12 mutants or wildtype activity is desired is contacted with an effective amount of a compound of Formula (II), or pharmaceutically acceptable salt of any one thereof and a CTLA-4 inhibitor to negatively modulate the activity of KRas G12 mutants or wildtype. In some cases, by negatively modulating the activity of KRas G12 mutants or wildtype, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12 mutants or wildtype activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12 mutants or wildtype. The ability of compounds to bind KRas G12 mutants or wildtype may be monitored in vitro using well known methods. [00550] In some embodiments, the inhibitory activity of exemplary compounds and a CTLA-4 inhibitor in cells may be monitored, for example, by measuring the inhibition of KRas G12 mutants or wildtype activity of the amount of phosphorylated ERK. [00551] In another aspect, methods of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound or salt of Formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided and a CTLA-4 inhibitor. [00552] The compositions and methods provided herein may be used for the treatment of a KRas G12 mutants or wildtype-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (II), a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a CTLA-4 inhibitor are provided. In some cases, KRas G12 mutants or wildtype associated cancer is lung cancer. [00553] The compositions and methods provided herein may be used for the treatment of a KRas G12D-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (II), a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a CTLA-4 inhibitor are provided. [00554] In some embodiments, the method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a CTLA-4 inhibitor and a compound or salt of Formula (II), synergistically increases the potency of the compound or salt of Formula (II). In some cases, the synergistic increase in potency of the compound or salt of Formula (II) results in an improved efficacy of the compound or salt of Formula (II). [00555] As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a KRas G12 mutants or wildtype with a compound provided herein and an immunomodulator inhibitor includes the administration of the compound provided herein and an immunomodulator inhibitor to an individual or patient, such as a human, having KRas G12D and/or other G12 mutants, as well as, for example, introducing a compound provided herein and an immunomodulator inhibitor into a sample containing a cellular or purified preparation containing the KRas G12D and/or other G12 mutants. [00556] The compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. In some cases, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer. In some cases, the cancer is non-small cell lung cancer. In some cases, the cancer is a solid tumor cancer. [00557] In some cases, the concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co- administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively. [00558] The compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject. [00559] The compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. [00560] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. [00561] In the case wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition. [00562] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. [00563] The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.02 - about 5000 mg per day, in some embodiments, about 1 – about 1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day. [00564] The pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The unit dosage may be in the form of a package containing discrete quantities of the formulation. Non- limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative. [00565] Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of 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 the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Compounds exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. [00566] In certain embodiments, the invention provides a method of treating or preventing a disease, state or condition in a patient in need thereof comprising administering to the patient an effective amount of a compound of any one of embodiments of the invention or a pharmaceutically acceptable salt thereof. The disease, state or condition may be selected from a group as described elsewhere herein. Bifunctional Compounds [00567] In some embodiments, compounds herein can adopt to selectively eliminate an over activated KRas signaling which is induced by KRas mutations by directly binding with the mutated KRas protein, either by stabilizing its GDP bound form (the inactive form) or by blocking the interaction between GTP bound form and its downstream target protein. In some embodiments, another way is to hijack the protein degradation mechanism in a cell and leverage E3 ligases’ (like VHL, CRBN or IAPs) substrate specificity through a bi-functional molecule called Proteolysis targeting chimera (PROTAC) (Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe- Paganon S, Bradner JE. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science.2015 Jun 19; 348 (6241): 1376-81), which can bind with both mutated KRas protein and E3 ligase, create interactions between those two proteins and induce KRas degradation. [00568] Disclosed herein is a bifunctional compound composed of a target protein (i.e., KRAS G12D)-binding moiety and an E3 ubiquitin ligase-binding moiety, which may induce proteasome- mediated degradation of selected proteins. In some embodiments, the bifunctional compound comprises a target protein (i.e., KRAS G12D)-binding moiety and an E3 ubiquitin ligase-binding moiety known in the art. In some embodiments, disclosed herein is the use of the compound disclosed herein in the preparation of degrading a target protein compound by using chemical modification of the compound disclosed herein. In some cases, the target protein-binding moiety is derived from a compound of Formula (I), Formula (II), Formula (II*), or Formula (III). Preparation of Compounds [00569] The compounds of the present disclosure can generally be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present disclosure can be synthesized using the methods described herein, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. The compounds of the present disclosure may be prepared as described in the schemes and examples described elsewhere herein. [00570] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope EXAMPLES [00571] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein. [00572] The present disclosure provides processes for preparing the compounds described herein (described in greater detail below). General Schemes Scheme IA
Figure imgf000207_0001
[00573] Treatment of R1 with methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate in the presence of a base such as DIEA in DCM can afford IA-a, which can be deprotonated with LDA or LiHMDS at -78 ^C in THF. IA-b can be formed by addition of a solution of a ketone in THF at -78 ^C and the reaction is quenched at -78 ^C. Ester IA-b can be reduced by DIBAL or LiAlH4 to diol IA-c, which can be cyclized into IA-d via Mitsunobu reaction or in the presence of BuLi and TsCl in THF at -78 ^C. Compound I can be prepared via Pd mediated coupling reactions or in the presence of a base such as NaH or LiHMDS. Scheme IB
Figure imgf000207_0002
[00574] Ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate can be deprotonated with LDA or LiHMDS at -78 ^C in THF. IB-a can be formed by addition of a solution of a ketone in THF at -78 ^C and the reaction is quenched at -78 ^C. Ester IB-a can be reduced by DIBAL or LiAlH4 to diol IB-b, which can be cyclized into IB-c via Mitsunobu reaction or in the presence of BuLi and TsCl in THF at -78 ^C. Treatment of R1 with IB-c can afford IB-d in the presence of a base such as DIEA in DCM can afford IB-d, which can be oxidized to sulfone IB-e. Compound I can be prepared via Pd mediated coupling reactions or in the presence of a base such as NaH or LiHMDS. Scheme IIA
Figure imgf000208_0001
[00575] Treatment of t-Butyl-sulfinimade and a ketone in the presence of Ti(OEt)4 can afford IIA-a. A solution of IIA-a in THF can be added to a solution of IA-a, deprotonated with LDA or LiHMDS at -78 ^C in THF, and the reaction can be quenched at -78 ^C to afford IIA-b. Ester IIA- b can be reduced by DIBAL or LiAlH4 to IIA-c, which can be cyclized into IIA-d via a sequence of removal of sufinimade under HCl, chorination of OH and cyclization in the presence of a base such as NaOH (ref. Garcia, D.; Moreno, B.; Soler, T.; Foubelo, F.; Yus, M. Tetrahedron Lett.2009, 50, 4710). R3 of IIA-e can be introduced via reductive amination or alkylation. Compound II can be prepared via Pd mediated coupling reactions or in the presence of a base such as NaH or LiHMDS. Scheme IIB
Figure imgf000208_0002
[00576] Ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate can be deprotonated with LDA or LiHMDS at -78 ^C in THF. IIB-a can be formed by addition of a solution of IIA-a in THF at -78 ^C and the reaction is quenched at -78 ^C. Ester IIB-a can be reduced by DIBAL or LiAlH4 to diol IIB-b, which can be cyclized into IIB-c as described in Scheme IIA above. R3 of IIB-d can be introduced via reductive amination or alkylation. Treatment of R1 with IIB-d can afford IIB-e in the presence of a base such as DIEA in DCM. IIB-e can be oxidized to sulfoxide IIB-f, which can be converted to II in the presence of a base such as NaH or LiHMDS. Example 1: Exemplary synthesis of 4'-(azepan-1-yl)-4-chloro-2'-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydrospiro[indene-1,7'-pyrano[4,3- d]pyrimidine] (compound 1)
Figure imgf000209_0001
[00577] Step 1: To a solution of methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate (1.0 g, 4.52 mmol, 1.0 eq) in ACN (7 mL) was added DIPEA (1.17 g, 9.05 mmol, 2.0 eq) and azepane (449 mg, 4.52 mmol, 1.0 eq) at 20 °C. Then the reaction was stirred at 20 °C for 2 hrs. TLC showed that the reaction was completed. The reaction was concentrated under vacuum. The residue was poured into water (20 mL). The aqueous phase was extracted with EtOAc (5 mL * 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE: EtOAc = 10:1) to give compound 1a (1.1 g, 3.88 mmol, 85.7% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 3.88 (s, 3H), 3.49-3.52 (m, 4H), 2.36 (s, 3H), 1.75-1.85 (m, 4H), 1.50- 1.60 (m, 4H). [00578] Step 2: To a solution of LDA (2 M, 2.11 mL, 1.2 eq) in THF (30 mL) was added compound 1a (1.0 g, 3.52 mmol, 1.0 eq) at -60°C. The mixture was stirred at -60 °C for 30 mins. 4-Chloro-2,3-dihydro-1H-inden-1-one (587 mg, 3.52 mmol, 1.0 eq) was added at -60 °C. The mixture was stirred at -60 °C for 1 hr. The reaction mixture was quenched by addition HCl (5%, 50 mL) at 0°C, and then extracted with EtOAc (20 mL * 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE: EtOAc = 5:1) to give compound 1b (0.5 g, 1.20 mmol, 33.9% yield) as a yellow solid. LCMS calcld for C22H25Cl2N3O3 (M+H)+m/z = 450.1; found 450.1. 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J =8.0 Hz, 1H), 7.13 (t, J =7.6 Hz, 1H), 7.03 (d, J =7.6 Hz, 1H), 6.06 (s, 1H), 3.69 (s, 3H), 3.47-3.54(m, 4H), 3.08-3.11 (m, 2H), 2.76-2.99 (m, 2H), 2.22-2.26 (m, 2H), 1.70-1.80 (m, 4H), 1.45-1.60 (m, 4H). [00579] Step 3: To a solution of compound 1b (490 mg, 1.09 mmol, 1.0 eq) in DCM (5 mL) was added DIBAL-H (1 M, 3.26 mL, 3.0 eq) at 0 °C. Then the reaction was stirred at 0 °C for 1 hr. The reaction mixture was quenched by H2O (20 ml) at 25°C. The mixture was extracted with DCM (10 mL * 2). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EtOAc=80/1 to 8/1 to give compound 1c (200 mg, 474 umol, 43.5% yield) as white solid. LCMS calcld for C21H25Cl2N3O2 (M+H)+m/z = 422.1; found 422.1. 1H NMR (400 MHz, CD3OD) δ 7.25 (d, J =8.0 Hz, 1H), 7.19 (t, J =7.6 Hz, 1H), 7.09 (d, J =7.6 Hz, 1H),4.40-4.44 (m, 1H), 4.29-4.32 (m, 1H), 3.78-3.81 (m, 4H), 3.25-3.26(m, 1H), 2.96-3.03 (m, 2H), 2.84-2.88 (m, 1H), 2.56-2.59 (m, 1H), 2.01-2.04 (m, 1H), 1.75-1.90 (m, 4H), 1.55-1.65 (m, 4H). [00580] Step 4: To a solution of compound 1c (200 mg, 474 umol, 1 eq) in THF (10 mL) was added PPh3 (149 mg, 568 umol, 1.2 eq) and DIAD (115 mg, 568 umol, 1.2 eq) at 0 °C under N2. Then the reaction was stirred at 0 °C for 2 hrs under N2. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE: EtOAc = 20:1) to give compound 1d (100 mg, 247 umol, 52.2% yield) as a yellow solid. C21H23Cl2N3O (M+H)+m/z = 404.1; found 404.1. 1H NMR (400 MHz, CDCl3) ^ 7.31 (d, J =8.0 Hz, 1H), 7.17 (t, J =7.6 Hz, 1H), 7.12 (d, J =7.6 Hz, 1H),4.65-4.71 (m, 1H), 4.51-4.53 (m, 1H), 3.50-3.65 (m, 4H), 3.07-3.17(m, 3H), 2.96-3.00 (m, 1H), 2.36-2.38 (m, 1H), 2.15-2.20 (m, 1H), 1.70-1.75 (m, 4H), 1.50-1.65 (m, 4H). [00581] Step 5: To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methanol (37.8 mg, 237 umol, 1.2 eq) in THF (2 mL) was added NaH (15.8 mg, 396 umol, 60% purity, 2.0 eq) at 0 °C. The reaction was stirred at 0 °C for 30 min. Then a solution of compound 1d (80 mg, 198 umol, 1.0 eq) in THF (0.5 mL) was added to the above solution at 0 °C. The reaction was continued to stir at 60 °C for 8 hrs. LC-MS showed 11% of starting material remained and 52.9% of desired compound was detected. The reaction was quenched with H2O (10 mL) at 0 °C. The aqueous phase was extracted with EtOAc (5 mL *2). The combined organic phase was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 6:1) to give 4'-(azepan-1-yl)-4-chloro- 2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5',8'- tetrahydrospiro[indene-1,7'-pyrano[4,3-d]pyrimidine] (compound 1, 11.0 mg, 20.8 umol, 10.5% yield) as yellow solid. C29H36ClFN4O2 (M+H)+m/z = 526.25; found 527.2.1H NMR (400 MHz, CDCl3) δ 7.10 (d, J =8.0 Hz, 1H), 6.90-7.00 (m, 2H), 5.00-5.40 (m, 1H), 4.50-4.53 (m, 1H), 4.32- 4.36 (m, 1H), 3.93-3.95 (m, 1H), 3.79-3.81 (m, 1H), 3.38-3.41 (m, 4H), 3.05-3.15(m, 2H), 2.90- 3.00 (m, 2H), 2.85-2.87(m, 1H), 2.70-2.80 (m, 2H), 2.15-2.25 (m, 1H), 1.95-2.10 (m, 4H), 1.50- 1.80 (m, 6H), 1.30-1.50 (m, 6H). Example 2. Exemplary synthesis of 4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-2'- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5',8'- tetrahydrospiro[indene-1,7'-pyrano[4,3-d]pyrimidine] (compound 2)
Figure imgf000211_0001
[00582] Step 1. Synthesis of tert-butyl 3-(2-chloro-5-methoxycarbonyl-6- methyl-pyrimidin-4- yl)-3,8-diaza- bicyclo[3.2.1]octane-8-carboxylate (2a). To a solution of methyl 2,4-dichloro-6- methyl-pyrimidine-5-carboxylate (200.0 mg, 0.9 mmol) in MeCN (4 mL) was added a mixture of DIEA (233.88 mg, 1.81 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (192.08 mg, 0.9 mmol) in DMF (1 mL) at 0 oC. The reaction mixture was stirred at 0 oC for 30 min under Ar. The solution was diluted with EtOAc (5 ml) and washed with H2O (5ml x3) and brine (5 ml). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluting with EtOAc:PE=1:7) to give tert-butyl 3-(2-chloro-5-methoxycarbonyl- 6-methyl-pyrimidin-4-yl)-3,8-diaza- bicyclo[3.2.1]octane-8-carboxylate (2a, 280 mg, 0.71 mmol, 78% yield) as a white solid. LCMS (ESI): m/z calcld for C18H25ClN4O4 +H: 397.87, found: 397.2. [00583] Step 2. Synthesis of tert-butyl 3-[2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin- 8-yl]methoxy]-5-methoxycarbonyl-6-methyl-pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (2b). To a degassed solution of tert-butyl 3-(2-chloro-5- methoxycarbonyl-6-methyl-pyrimidin-4-yl)-3,8-diaza- bicyclo[3.2.1]octane-8-carboxylate (2a, 400.0 mg, 1.01 mmol) in toluene (15 mL) were added [(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methanol (332.67 mg, 2.09 mmol), Ruphos (97.5 mg, 0.21 mmol), Pd2(dba)3 (95.71 mg, 0.1 mmol) and Cs2CO3 (851.06 mg, 2.61mmol). The degassed mixture was stirred at 110 °C for 16 h under Ar. The reaction mixture was concentrated under reduced pressure to give crude product which was purified by silica gel chromatography column (EtOAc:PE = 1:1 to DCM:MeOH=10:1) to obtain tert-butyl 3-[2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5-methoxycarbonyl-6-methyl-pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (2b, 460mg, 0.88 mmol, 88% yield) as a sticky brown solid. LCMS (ESI): m/z calcld for C26H38FN5O5+H: 520.2, found: 520.2. [00584] Step 3. Synthesis of tert-butyl 3-[6-[(4-chloro-1-hydroxy-indan- 1-yl)methyl]-2- [[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5-methoxycarbonyl- pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2c). To a solution of tert-butyl 3- [5-methoxycarbonyl-6-methyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2b, 150.0 mg, 0.29 mmol) in THF (15 mL) at -70 °C was added LDA (0.72 mL, 1.44 mmol, 2 mol/L in THF) dropwise. The reaction mixture was stirred between -70 °C to -20 °C for 1.5 h under Ar. Then a solution of 4-chloroindan-1-one (240.47 mg, 1.44 mmol) in THF (3 mL) was added dropwise to the above resulting solution at -70 °C. The reaction mixture was stirred between -70 °C to 0 °C for 3 h under Ar. The reaction mixture was quenched by aqueous NH4Cl solution at -50 oC, and extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuo to give the crude product which was purified on prep-TLC (DCM:MeOH=10:1) to give tert-butyl 3-[6-[(4-chloro-1-hydroxy-indan-1-yl)methyl]-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5-methoxycarbonyl- pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2c, 75 mg, 0.11 mmol, 38% yield) as a light yellow sticky solid. LCMS (ESI): m/z calcld for C35H45ClFN5O6+H: 686.1, found: 686.2. [00585] Step 4. Synthesis of tert-butyl 3-[6-[(4-chloro-1-hydroxy-indan-1-yl)methyl]-2- [[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5- (hydroxymethyl)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2d). To a degassed solution of tert-butyl 3-[6-[(4-chloro-1-hydroxy-indan-1-yl)methyl]-5 - methoxycarbonyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2c, 120.0 mg, 0.17 mmol) in anhydrous THF (8 mL) at -70 °C was added dropwise DIBAL-H (2.91 mL, 4.37 mmol) at -70 °C. The mixture was warmed to 0 °C naturally and stirred for 16 h under Ar. The reaction mixture was quenched by aqueous NH4Cl solution at 0 °C, and extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuo to give crude product which was purified on Pre-TLC (DCM:MeOH = 10:1) to give tert-butyl 3-[6-[(4- chloro-1-hydroxy-indan-1-yl)methyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-5-(hydroxymethyl)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2d, 60 mg, 0.091 mmol, 52.1% yield) as a colorless sticky solid. LCMS (ESI): m/z calcld for C34H45ClFN5O5 +H: 658.3, found: 658.3. [00586] Step 5. Synthesis of tert-butyl 3-[4'-chloro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8-yl] methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4- yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2e). To a degassed mixture of tert-butyl 3-[6- [(4-chloro-1-hydroxy-indan-1-yl)methyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]-5-(hydroxymethyl)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2d, 70.0 mg, 0.11mmol) and DIPEA (0.04 mL, 0.23mmol) in anhydrous THF (5 mL) at 0 °C was added MsCl (60.92 mg, 0.53 mmol) dropwise. The degassed mixture was warmed to 10 °C and stirred for 16 h under Ar. The mixture was quenched by aqueous NaHCO3 solution and extracted with EtOAc, washed with water and brine. The organics was dried over anhydrous Na2SO4, filtered and concentrated under vacuo. The residue was purified by Pre-TLC (DCM:MeOH = 15:1) to give crude product (2e, 65 mg) as a sticky brown solid. LCMS (ESI): m/z calcld for C34H43ClFN5O4+H: 640.3, found: 640.2. [00587] Step 6. Synthesis of 4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-2'- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5',8'- tetrahydrospiro[indene-1,7'-pyrano[4,3-d]pyrimidine] (2). To a solution of tert-butyl 3-[4'- chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydro- pyrrolizin-8-yl]methoxy]spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (64.0 mg, 0.1 mmol) in DCM (1.5 mL) was added TFA (2.95 mL, 39.77mmol). The mixture was stirred at rt. for 20 min. The mixture was concentrated under vacuo to afford the crude product which was purified by Prep-HPLC (eluted with CH3CN in H2O (0.1 % TFA) from 5.0% to 95%). Then the preparation solution is treated with 1N hydrochloric acid to replace TFA to give 4'-chloro-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'- indane];dihydrochloride (12.32 mg, 0.0141mmol, 14% yield) as a white solid. LCMS (ESI): m/z calcld for C29H35ClFN5O2+H: 540.2, found: 540.2.1H NMR (400 MHz, CD3OD) δ 7.37 (m, 3H), 5.59 (dd, J = 52.0, 13.6 Hz, 1H), 5.07 (d, J = 13.9 Hz, 1H), 4.69 – 4.35 (m, 3H), 4.35 – 4.06 (m, 3H), 3.90 (m, 6H), 3.42 (s, 2H), 3.26 – 3.07 (m, 2H), 3.00 (s, 1H), 2.88 – 1.99 (m, 12H). Example 3. Exemplary synthesis of (4'-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-2'-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[2H-indeno[1,2-c]pyrazole-4,7'-5,8- dihydropyrano[4,3-d]pyrimidine] (compound 3)
Figure imgf000214_0001
[00588] Step 1. Synthesis of 4-hydrazono-2,4-dihydroindeno[1,2-c]pyrazole (3a). To a solution of indane-1,3-dione (5.00 g, 34.2 mmol, 1.0 eq) in THF (50 mL) was added DMF-DMA (4.15 g, 34.9 mmol, 1.02 eq) dropwise. The resulting mixture was stirred at^room temperature^for 1 h. TLC showed SM was consumed. The mixture was concentrated in vacuo to afford crude 2- (dimethylaminomethylene)indane-1,3-dione (3a.6.87 g, 34.1 mmol, crude) as a black solid, which was used in next step directly without further purification. LCMS calcld for^C12H12NO2^(M+H)+^m/z =202.1; found: 202.1. [00589] Step 2. Synthesis of 4-hydrazono-2,4-dihydroindeno[1,2-c]pyrazole (3b). To a solution of 2-(dimethylaminomethylene)indane-1,3-dione (3a, 6.87 g, 34.1 mmol, crude) in AcOH (10.0 mL) was added hydrazine hydrate (10.0 mL, 205 mmol, 5.0 eq) drop wise. Then the mixture was stirred at 90 ℃ for 16 h and the solvent was removed in vacuo. The residue was suspended in water (30 mL), and the solid was collected by filtration, washed with water (90 mL) and aq. NaHCO3 (90 mL), and dried in vacuo to afford 4-hydrazono-2,4-dihydroindeno[1,2- c]pyrazole (3b, 5.23 g, 30.7 mmol, 89.9% yield over two steps) as a yellow solid. LCMS calcld for C10H9N4 (M+H) m/z =185.0; found: 185.0. [00590] Step 3. Synthesis of 2H-indeno[1,2-c]pyrazol-4-one (3c). A solution of^NaIO4 (9.59 g, 44.8 mmol, 2.0 eq) in^water (100 mL) and^EtOAc (100 mL) was stirred at room temperature for 5 min. Then^2,4-dihydroindeno[1,2-c]pyrazol-4-yldiazene (3b, 4.13 g, 22.4 mmol) was added, the resulting mixture was stirred at room temperature for 2h.^^The mixture was extracted with EtOAc (100 mL*3), the combined organic phase was concentrated and purified^by flash chromatography (silica gel, eluted with EtOAc in PE 0 to 30%) to give the 2H-indeno[1,2-c]pyrazol-4-one (3c, 1.74 g, 10.2 mmol, 45.6% yield) as a white solid. LCMS calcld for C10H7N2O (M+H) m/z =171.0; found: 171.0. [00591] Step 4. Synthesis of 2-(2-trimethylsilylethoxymethyl)indeno[1,2-c]pyrazol-4-one (3d). To a solution of 2H-indeno[1,2-c]pyrazol-4-one (800 mg, 4.70 mmol, 1.0 eq) in DMF (12 mL) was added NaH (3c, 169 mg, 7.05 mmol, 1.5 eq) at 0℃, the mixture was stirred at the same temperature for 30 min, then SEMCl (1.17 g, 7.05 mmol, 1.5 eq) was added. The resulting mixture was allowed to warm to room temperature and stirred for 1h. The reaction was quenched with NH4Cl (aq) and extracted with EtOAc (50 mL*3), the combined organic phase was concentrated and purified by flash chromatography (silica gel, eluted with EtOAc in PE 0 to 25%) to give a mixture of 2-(2-trimethylsilylethoxymethyl)indeno[1,2-c]pyrazol-4-one and its regioisomer (not shown) (3d, 1.38 g, 4.60 mmol, 97% yield) as a yellow solid. LCMS calcld for C16H21N2O2Si (M+H) m/z = 301.1; found: 301.0. [00592] Step 5. Synthesis of tert-butyl (1S,5R)-3-[2-chloro-6-[[4-hydroxy-2-(2- trimethylsilylethoxymethyl)indeno[1,2-c]pyrazol-4-yl]methyl]-5-methoxycarbonyl-pyrimidin-4- yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3e). To a solution of^tert-butyl rac-(1S,5R)-3- (2-chloro-5-methoxycarbonyl-6-methyl-pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (2a, 800 mg, 2.02 mmol, 1.0 eq) in^dry THF (6 mL) was added^LDA (1.21 mL, 2.42 mmol, 1.2 eq, 2M in THF/n-heptane) dropwise at^-70^℃ under N2, the mixture was stirred at^the same temperature for 0.5 h^,then^2-(2-trimethylsilylethoxymethyl)indeno[1,2-c]pyrazol-4-one (3d, 667 mg, 2.22 mmol, 1.1 eq) in^dry THF (6 mL) was added drop wise. The mixture was stirred^at^the same temperature^for 1h and then quenched with NH4Cl (aq.). The residue was extracted with EtOAc (20 mL*3) and^the^organic phase was concentrated in vacuum. The residue was purified by flash chromatography (silica gel, Eluant with EtOAc in PE 0 to 50%) to afford tert-butyl (1S,5R)-3-[2-chloro-6-[[4-hydroxy-2-(2-trimethylsilylethoxymethyl)indeno[1,2- c]pyrazol-4-yl]methyl]-5-methoxycarbonyl-pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (3e, 1.20 g, 1.72 mmol, 85.4% yield) ^as^a white solid. LCMS calcld for C34H46ClN6O6Si (M+H)+^m/z =697.3; found:^697.5. [00593] Step 6. Synthesis of 4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5',8'-dihydro-2H-spiro[indeno[1,2- c]pyrazole-4,7'-pyrano[4,3-d]pyrimidine] (3f). To a solution of tert-butyl (1R,5S)-3-[2-chloro-6- [[4-hydroxy-2-(2-trimethylsilylethoxymethyl)indeno[1,2-c]pyrazol-4-yl]methyl]-5- methoxycarbonyl-pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3e, 670 mg, 0.960 mmol, 1.0 eq) in dry DCM (5 mL) was added DIBAL-H (2.56 mL, 3.84 mmol, 4.0 eq, 1.5 M in toluene) at 0 ℃ under N2, the resulting mixture was stirred at same temperature for 1 h and then quenched with H2O. The mixture was extracted with EtOAc (50 mL*3) and the organic phase was concentrated and purified by flash column chromatography (silica gel, eluting EtOAc in PE 0 to 50%). The desired fractions were concentrated to dryness in vacuo to afford tert-butyl (1R,5S)-3-[2-chloro-5-(hydroxymethyl)-6-[[4-hydroxy-2-(2- trimethylsilylethoxymethyl)indeno[1,2-c]pyrazol-4-yl]methyl]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (3f, 320 mg, 0.478 mmol, 49.8% yield). LCMS calcld for C33H46ClN6O5Si (M+H)+ m/z = 669.3; found: 669.2. [00594] Step 7. Synthesis of tert-butyl (1R,5S)-3-[2-chloro-2'-(2- trimethylsilylethoxymethyl)spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,4'-indeno[1,2- c]pyrazole]-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3g). To a solution of^tert-butyl (1R,5S)-3-[2-chloro-5-(hydroxymethyl)-6-[[4-hydroxy-2-(2- trimethylsilylethoxymethyl)indeno[1,2-c]pyrazol-4-yl]methyl]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (3f, 67.0 mg, 0.100 mmol, 1.0 eq) in^dry THF (1.50 mL) was added n-BuLi (0.042 mL, 0.11 mmol, 1.05 eq, 2.5 M in THF) under N2 at^-78^℃, then stirred for 1 h. A solution of TsCl (21.0 mg, 0.110 mmol, 1.05 eq) in^dry THF (1.50 mL) was added slowly, the mixture was allowed warm to 0 ℃ and stirred for 30 min, then^it was cooled to -78 ℃ and n-BuLi (0.042 mL, 0.11 mmol, 1.05 eq, 2.5 M in THF) was added. After it was stirred at the same temperature for 10 min, the mixture was allowed to warm to room temperature and stirred for 1h.^Then^it was quenched by the addition of^H2O (2 mL) and^extracted with EtOAc (10 mL*3), the organic phase was concentrated and purified by^flash column chromatography (silica gel, eluting EtOAc in PE 0 to 25%). The desired fractions were concentrated to dryness in vacuo to afford tert-butyl (1R,5S)-3-[2-chloro-2'-(2-trimethylsilylethoxymethyl)spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,4'-indeno[1,2-c]pyrazole]-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (3g, 49.0 mg, 0.0752 mmol, 75.2% yield) as a yellow oil.^ LCMS calcld for C33H44ClN6O4Si (M+H)+^m/z =651.3; found: 651.3. [00595] Step 8. Synthesis of tert-butyl (1R,5S)-3-[2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-2'-(2-trimethylsilylethoxymethyl)spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,4'-indeno[1,2-c]pyrazole]-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (3h). A^mixture of^[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methanol (35.9 mg, 0.230 mmol, 3.0 eq), Pd2(dba)3 (6.89 mg, 0.0100 mmol, 0.1 eq), Ruphos (7.02 mg, 0.0200 mmol, 0.2 eq), Cs2CO3 (738 mg, 0.230 mmol, 3.0 eq) and tert-butyl (1R,5S)-3-[2-chloro-2'-(2-trimethylsilylethoxymethyl)spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,4'-indeno[1,2-c]pyrazole]-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (3g, 49.0 mg, 0.0800 mmol, 1.0 eq)^in^Toluene (3 mL) was charged with N2^ for 3 times. The resulting mixture was heated to 110 ℃ for 16 h. The resulting solution was cooled to rt and filtered, and then the filtrate was concentrated and purified by^flash column chromatography (silica gel, eluting MeOH^in DCM 0 to 10%). The desired fractions were concentrated to dryness in vacuo^to afford tert-butyl (1R,5S)-3-[2-[[rac-(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-2'-(2- trimethylsilylethoxymethyl)spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,4'-indeno[1,2- c]pyrazole]-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3h, 51.0 mg, 0.0659 mmol, 87.6% yield) as a yellow solid.^ LCMS calcld for C41H57FN7O5Si(M+H)+^m/z =774.4; found:^774.6. [00596] Step 9. Synthesis of 4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5',8'-dihydro-2H-spiro[indeno[1,2- c]pyrazole-4,7'-pyrano[4,3-d]pyrimidine] (3). To a solution of^tert-butyl rac-(1R,5S)-3-[2-[[rac- (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-2'-(2- trimethylsilylethoxymethyl)spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,4'-indeno[1,2- c]pyrazole]-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (51.0 mg, 0.0700 mmol, 1.0 eq) in^MeCN (1 mL) was added^HCl in dioxane (1.00 mL, 4.00 mmol, 4 M). The resulting mixture was stirred at room temperature for 5h.^The solvent was removed by N2 and the residue was purified by^Prep-HPLC on a C18 column (5 uM, 50^x^150 mm) with mobile phase: H2O (0.1% NH4HCO3) / MeOH at flow rate : 35 mL/min to afford 4'-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan- 3-yl]-2'-[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[2H-indeno[1,2- c]pyrazole-4,7'-5,8-dihydropyrano[4,3-d]pyrimidine] (7.28 mg, 0.0134 mmol, 20.3% yield) as a yellow solid.^ LCMS calcld for C30H35FN7O2(M+H)+ m/z =544.3; found:^544.5. 1H NMR (400 MHz, CD3OD) δ 7.63 (d,J^= 7.2 Hz, 1H), 7.53 (d,J^= 7.6 Hz, 1H), 7.40 - 7.47 (m, 2H), 7.36 (t,J^= 7.2 Hz, 1H), 5.28 (d,J^= 52.0 Hz, 1H), 4.97 (d,J^= 13.6 Hz, 1H), 4.79 - 4.82 (m, 1H), 4.03 - 4.21 (m, 3H), 3.73 (d,J^= 12.4 Hz, 1H), 3.59 (s, 2H), 3.50 (d,J^= 17.6 Hz, 1H), 3.40 (d,J^= 12.8 Hz, 1H), 3.11 - 3.26 (m, 4H), 2.95 - 3.05 (m, 1H), 2.63 (d,J^= 17.6 Hz, 1H), 1.78 - 2.13 (m, 10H). [00597] Compound 4.1-[7'-bromo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]azepan-4-ol
Figure imgf000217_0001
[00598] Compound 4 was prepared similar to that of Ex.1 as a dihydrochloride salt. LCMS calcld for C30H38BrFN4O3 (M+H)+ m/z = 601.2; found : 601.2.1H NMR (400 MHz, CD3OD) δ 7.65-7.57 (m, 1H), 7.41-7.32 (m, 1H), 7.13-7.04 (m, 1H), 5.69-5.20 (m, 1H), 5.09- 5.00 (m, 1H), 4.85-4.72 (m, 3H), 4.04-3.78 (m, 8H), 3.51-3.39 (m, 1H), 3.19-3.98 (m, 2H), 2.86- 2.58 (m, 4H), 2.50-2.41 (m, 1H), 2.41-1.67 (m, 13H). [00599] Compound 5.4-(azepan-1-yl)-5'-bromo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-tetralin].
Figure imgf000218_0001
[00600] Compound 5 was prepared similar to that of Ex.1 as a TFA salt. LCMS (ESI)：m/z calcld for C30H38BrFN4O2+H: 587.2, found: 587.2.1H NMR (400 MHz, CD3OD) δ 7.55 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 6.9 Hz, 1H), 7.14 (t, J = 7.2 Hz, 1H), 5.59 (d, J = 51.6 Hz, 1H), 4.99 (d, J = 12.0 Hz, 1H), 4.74 (d, J = 14.8 Hz, 3H), 3.89 (dd, J = 38.2, 24.9 Hz, 6H), 3.54 – 3.37 (m, 1H), 3.17 (dd, J = 18.1, 6.4 Hz, 1H), 3.06 (d, J = 18.2 Hz, 1H), 2.92 (d, J = 17.4 Hz, 1H), 2.81 – 2.73 (m, 1H), 2.64 (d, J = 19.6 Hz, 2H), 2.45 (s, 1H), 2.35 (s, 2H), 2.19 (d, J = 16.4 Hz, 3H), 2.06 – 1.81 (m, 6H), 1.65 (d, J = 28.8 Hz, 4H). [00601] Compound 6.1-[4'-chloro-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]azepan-4-ol.
Figure imgf000218_0002
[00602] Compound 6 was prepared similar to that of Ex.1 as a dihydrochloride salt. LCMS (ESI): m/z calcld for C29H37ClFN4O3 +H: 543.4, found: 543.4.1H NMR (400 MHz, CD3OD) δ 7.37 (d, J = 8.8 Hz, 1H), 7.32 – 7.22 (m, 2H), 5.59 (d, J = 51.4 Hz, 1H), 4.94 – 4.89 (m, 1H), 4.82 – 4.72 (m, 2H), 4.64 (dd, J = 14.9, 5.4 Hz, 1H), 4.09 – 3.73 (m, 8H), 3.52 – 3.41 (m, 1H), 3.20 – 3.07 (m, 3H), 3.05 – 2.94 (m, 1H), 2.77 – 2.58 (m, 3H), 2.49 – 2.29 (m, 5H), 2.27 – 2.07 (m, 3H), 1.97 – 1.74 (m, 4H). [00603] Compound 7 & compound 8.4-(azepan-1-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,4'-tetralin]-6'-ol, isomer 1 & 2.
Figure imgf000219_0001
[00604] Compound 7 and compound 8 were prepared similar to that of Ex.1 separated by reverse phase HPLC. LCMS (ESI)：m/z calcld for C30H39FN4O3 +H: 523.1, found: 523.1.1H NMR (400 MHz, CD3OD, isomer 1, compound 7) δ 6.96 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 2.3 Hz, 1H), 6.67 (dd, J = 8.3, 2.4 Hz, 1H), 5.29 (d, J = 54.4 Hz, 1H), 4.81 (d, 1H), 4.58 (d, 1H), 4.17 (d, 1H), 4.08 (d, 1H), 3.65 (t, 4H), 3.30 – 3.13 (m, 3H), 3.01 (dd, 2H), 2.94 – 2.82 (m, 1H), 2.74 (qd, 2H), 2.26 (ddd, 2H), 2.13 – 1.93 (m, 6H), 1.91 – 1.71 (m, 6H), 1.59 (d, J = 3.3 Hz, 4H).1H NMR (400 MHz, CD3OD, isomer 2, compound 8) δ 6.94 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 2.3 Hz, 1H), 6.65 (dd, J = 8.3, 2.4 Hz, 1H), 5.27 (d, J = 54.4 Hz, 1H), 4.79 (d, J = 14.2 Hz, 1H), 4.56 (d, J = 14.1 Hz, 1H), 4.15 (d, J = 10.4 Hz, 1H), 4.06 (d, J = 10.4 Hz, 1H), 3.72 – 3.56 (m, 4H), 3.29 – 3.13 (m, 3H), 3.04 – 2.94 (m, 2H), 2.85 (d, J = 17.8 Hz, 1H), 2.80 – 2.63 (m, 2H), 2.32 – 1.77 (m, 14H), 1.65 – 1.51 (m, 4H). [00605] Compound 9.4-(azepan-1-yl)-7'-chloro-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,3'-indane]-4'-ol.
Figure imgf000219_0002
[00606] Compound 9 was prepared similar to that of Ex.1 as a TFA salt. LCMS m/z calcld for C29H36ClFN4O3+H: 543.1, found:543.2.1H NMR (400 MHz, CD3OD) δ 7.13 (d, J = 8.6 Hz, 1H), 6.66 (d, J = 8.6 Hz, 1H), 5.57 (d, J = 51.3 Hz, 1H), 4.75 (d, J = 14.1 Hz, 1H), 4.70 – 4.50 (m, 3H), 4.00 – 3.74 (m, 5H), 3.75 – 3.63 (m, 2H), 3.52 – 3.44 (m, 1H), 3.38 – 3.34 (m, 1H), 3.09 – 2.96 (m, 2H), 2.90-2.86 (m, 1H), 2.71 – 2.63 (m, 1H), 2.62 – 2.56 (m, 1H), 2.45 – 2.31 (m, 4H), 2.27 – 2.13 (m, 2H), 2.00 – 1.75 (m, 4H), 1.69 – 1.48 (m, 4H).19F NMR (377 MHz, CD3OD) δ -174.17. [00607] Compound 10.5'-bromo-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'- tetralin]
Figure imgf000220_0001
[00608] Compound 10 was prepared similar to that of Ex.2 as a dihydrochloride salt. LCMS (ESI)：m/z calcld for C30H37BrFN5O2 +H: 598.2, found: 598.2.1H NMR (400 MHz, CD3OD) δ 7.57 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 5.62 (d, J = 52.1 Hz, 1H), 5.01 (dd, 1H), 4.86 (s, 2H), 4.73 (s, 1H), 4.70 (s, 1H), 4.40 (t, 1H), 4.25 (s, 2H), 4.04 – 3.84 (m, 4H), 3.73 (d, 1H), 3.47 (td, 1H), 3.24 (dd, 1H), 3.15 (d, 1H), 2.94 (d, 1H), 2.87 – 2.75 (m, 2H), 2.74 – 2.59 (m, 2H), 2.53 (d, 1H), 2.39 (dd, 2H), 2.27 (s, 2H), 2.15 (s, 5H), 2.03 (t, 1H), 1.88 (s, 1H). [00609] Compound 11.1-[7'-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]azepan-4- ol;dihydrochloride
Figure imgf000220_0002
[00610] Compound 11 was prepared similar to that of Ex.1 as a dihydrochloride salt. LCMS m/z calcld for C30H38F2N4O3 +H 541.2, found 541.2.1H NMR (400 MHz, CD3OD) δ 7.22 – 7.12 (m, 2H), 6.98 (dd, J = 9.7, 7.1 Hz, 1H), 5.59 (d, J = 51.7 Hz, 1H), 5.04 (d, J = 14.2 Hz, 1H), 4.77 (d, J = 9.4 Hz, 3H), 4.07 – 3.72 (m, 8H), 3.47 (s, 1H), 3.09 (dt, J = 34.3, 14.2 Hz, 2H), 2.83 (s, 2H), 2.61 (s, 2H), 2.45 (s, 1H), 2.35 (s, 2H), 2.15 (d, 6H), 1.89 (dd, 6H). [00611] Compound 12.4-(azepan-1-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-tetralin]
Figure imgf000220_0003
[00612] Compound 12 was prepared similarly to that of Ex.1 as a dihydrochloride salt. LCMS (ESI)：m/z calcld for C30H39FN4O2 +H; 507.2, found; 507.2.1H NMR (400 MHz, CD3OD) δ 7.32 (d, J = 7.7 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 7.07 (t, J = 7.0 Hz, 2H), 5.49 (d, J = 51.3 Hz, 1H), 4.90 – 4.84 (m, 1H), 4.69 – 4.62 (m, 2H), 4.62 – 4.53 (m, 1H), 3.92 – 3.72 (m, 6H), 3.40 – 3.31 (m, 1H), 3.12 – 3.00 (m, 1H), 2.95-2.89 (m, 1H), 2.82 – 2.69 (m, 2H), 2.63 – 2.55 (m, 1H), 2.54 – 2.48 (m, 1H), 2.41 – 2.31 (m, 1H), 2.30 – 2.19 (m, 2H), 2.14 – 2.06 (m, 2H), 2.00 – 1.91 (m, 2H), 1.84 – 1.45 (m, 10H). Example 4. Exemplary synthesis of 1-[7'-amino-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-tetralin]-4- yl]azepan-4-ol (Compound 13)
Figure imgf000221_0001
[00613] Step 1. Synthesis of 1-[7'-(benzhydrylideneamino)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-tetralin]-4- yl]azepan-4-ol (13a). The solution of Pd2dba3 (4.57mg, 0.mmol), diphenylmethanimine (18.08mg, 0.1mmol), t-BuONa (9.58mg, 0.1mmol), BINAP (2.11mg, 0.01mmol) and 1-[7'- bromo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]azepan-4-ol (4, 30.mg, 0.05mmol) in Toluene (2mL) was stirred at 100 °C under N2 for 6h. The mixture was concentrated and purified by prep-HPLC (eluted with CH3CN in H2O (0.1% NH4HCO3) from 5% to 95%) to obtain 1-[7'- (benzhydrylideneamino)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]azepan-4-ol (13a, 10mg,0.014mmol, 29% yield) as a brown solid. LCMS calcld for C43H48FN5O3 (M+H)+ m/z = 702.8; found; 702.4. [00614] Step 2. Synthesis of 1-[7'-amino-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-tetralin]-4- yl]azepan-4-ol (13). The solution of NH2NHOH.HCl (2.97mg, 0.04mmol), AcONa (3.5mg, 0.04mmol) and 1-[7'-(benzhydrylideneamino)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-tetralin]-4- yl]azepan-4-ol (13a, 10.mg, 0.01mmol) in Methanol (1mL) was stirred at 25 oC under N2 for 16h. The reaction was concentrated to get the crude, which was then purified by prep-HPLC (eluted with CH3CN in H2O (0.1% TFA) from 5% to 95%), then exchanged with HCl before lyophilization to give 1-[7'-amino-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]azepan-4- ol;dihydrochloride (13, 2.43mg, 0.0037mmol, 26.3% yield) as yellow solid. LCMS calcld for C30H40FN5O3 (M+H)+ m/z = 538.3; found; 538.3.1H NMR (400 MHz, CD3OD) δ 7.60-7.50 (m, 1H), 7.40-7.21 (m, 2H), 5.69-5.50 (m, 1H), 5.08-4.98 (m, 1H), 4.85-4.65 (m, 4H), 4.05-3.70 (m, 8H), 3.51-3.39 (m, 1H), 3.17-3.06 (m, 2H), 2.95-2.85 (m, 2H), 2.77-2.58 (m, 2H), 2.50-2.00 (m, 9H), 1.96-1.73 (m, 4H). [00615] Compound 14.2-[[(2S,8R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]- 4-(4-hydroxyazepan-1-yl)spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,4'-tetralin]-6'-ol
Figure imgf000222_0001
[00616] Compound 14 was prepared similarly to that of Ex.1 as a formic acid salt. LCMS (ESI)：m/z calcld for C30H39FN4O4 +H; 539.1; found 539.1.1H NMR (400 MHz, CD3OD) δ 8.51 (s, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.79 – 6.72 (m, 1H), 6.66 (dd, J = 8.3, 2.4 Hz, 1H), 5.39 (d, J = 53.6 Hz, 1H), 4.82 – 4.76 (m, 1H), 4.64 – 4.54 (m, 1H), 4.30 (dd, J = 10.9, 2.7 Hz, 1H), 4.25 – 4.16 (m, 1H), 3.91 – 3.51 (m, 6H), 3.49 – 3.39 (m, 2H), 3.23 – 3.10 (m, 1H), 3.00 (d, J = 17.6 Hz, 1H), 2.86 (d, J = 17.8 Hz, 1H), 2.80 – 2.65 (m, 2H), 2.54 – 2.21 (m, 3H), 2.21 – 1.87 (m, 8H), 1.88 – 1.56 (m, 5H).19F NMR (377 MHz, CD3OD) δ -173.75. [00617] Compound 15.1-[5'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]azepan-4-ol
Figure imgf000222_0002
[00618] Compound 15 was prepared similarly to that of Ex.1 as a formic acid salt. LCMS (ESI)：m/z calcld for C30H38ClFN4O3 +H: 557.1; found: 557.1.1H NMR (400 MHz, DMSO) δ 7.37 (t, J = 6.7 Hz, 2H), 7.21 (t, J = 7.9 Hz, 1H), 5.25 (d, J = 54.5 Hz, 1H), 4.78 (t, 1H), 4.55 (d, 1H), 4.02 – 3.90 (m, 1H), 3.85 (dd, 1H), 3.66 (s, 3H), 3.13 – 2.66 (m, 10H), 2.11 – 1.41 (m, 16H). Example 5. Exemplary synthesis of 1-(4-chloro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)- 2,3,5',8'-tetrahydrospiro[indene-1,7'-pyrano[4,3-d]pyrimidin]-4'- yl)azepane-4-carbonitrile (Compound 16)
Figure imgf000223_0001
[00619] Step 1. Preparation of 1-(4-chloro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl) methoxy)-2,3,5',8'-tetrahydrospiro[indene-1,7'-pyrano[4,3-d]pyrimidin]-4'-yl)azepan- 4-yl methanesulfonate (16a). The mixture of 1-[4'-chloro-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl] methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4- yl]azepan-4-ol;dihydrochloride (15.0 mg, 0.02mmol), methanesulfonyl chloride (0.02mL, 0.29mmol) and N,N-diethylethanamine (0.05mL, 0.37mmol) in DCM (1 mL) was stirred at 25 oC for 30 min. The mixture was concentrated to afford a crude product which was purified on silica gel column eluted with EtOAc in PE from 5% to 50% to afford 1-[4'-chloro-2-[[rac- (2R,8S)-2-fluoro-1,2,3,5,6,7-hexa- hydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3- d]pyrimidine-7,1'-indane]-4-yl]azepan-4-yl] methanesulfonate (16a, 15 mg, 0.0241 mmol, 99.2% yield) as yellow sticky solid. LCMS calcld for C30H38ClFN4O5S (M+H)+ m/z = 621.3, found; 621.3. [00620] Step 2. Preparation of 1-(4-chloro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl)methoxy)-2,3,5',8'-tetrahydrospiro[indene-1,7'-pyrano[4,3-d]pyrimidin]-4'-yl)azepane-4- carbonitrile (16). The mixture of [1-[4'-chloro-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy] spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4- yl]azepan-4-yl]methanesulfonate (65.0 mg, 0.1 mmol), 18-crown-6 (27.66 mg, 0.1 mmol) and NaCN (51.29 mg, 1.05mmol) was stirred at 25 ºC for 16 h. The mixture was diluted with EtOAc (2 mL), washed with water (1 mL) and brine (1 ml), dried over Na2SO4, concentrated. The crude product was purified by prep-HPLC (eluted with CH3CN in H2O (0.1 % FA)) from 5.0% to 95% to afford 1-[4'-chloro-2-[[rac-(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]azepane-4- carbonitrile;formic acid (16, 11.79 mg, 0.0193 mmol, 18.43 % yield) as white solid. LCMS calcld for C30H36ClFN5O2 (M+H)+ m/z =552.2, found: 552.2.1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.31 – 7.10 (m, 3H), 5.34 (d, J = 54.1 Hz, 1H), 4.73 – 4.55 (m, 2H), 4.26 – 4.17 (m, 2H), 3.83 – 3.62 (m, 3H), 3.58 – 3.34 (m, 4H), 3.14 – 2.89 (m, 6H), 2.40 – 1.91 (m, 14H). [00621] Compound 17.1-(7-chloro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-3,4,5',8'-tetrahydro-2H-spiro[naphthalene-1,7'-pyrano[4,3-d]pyrimidin]-4'- yl)azepan-4-ol
Figure imgf000224_0001
[00622] Compound 17 was prepared similarly to that of Ex.1 as a formic acid salt. LCMS calcld for C30H38ClFN4O3 (M+H)+ m/z = 557.2, found: 557.2.1H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.21 – 7.16 (m, 1H), 7.12 (dd, J = 8.2, 3.4 Hz, 1H), 5.33 (d, J = 53.3 Hz, 1H), 4.65 – 4.60 (m, 1H), 4.24 – 4.14 (m, 2H), 3.74 - 3.55 (m, 6H), 3.15 – 3.03 (m, 1H), 2.94 – 2.87 (m, 2H), 2.94 – 2.89 (m, 2H), 2.88 – 2.79 (m, 2H), 2.29 – 2.15 (m, 1H), 2.12 – 1.92 (m, 8H), 1.91 – 1.63 (m, 6H). [00623] Compound 18.4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-4-(2,3,6,7-tetrahydroazepin-1-yl)spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'- indane]
Figure imgf000224_0002
[00624] Compound 18 was prepared similarly to that of Ex.1 as a TFA salt. LCMS (ESI)： m/z calcld for C29H34ClFN4O2+H: 525.06, found:525.2. H NMR (400 MHz, CDCl3) δ 7.27-7.22 (m, 1H), 7.12-7.02 (m, 2 H), 7.03 -6.99 (s, 1H), 5.67 (s, 2H), 5.49 (d, J = 53.2 Hz, 1H), 5.04-4.91 (m, 1H), 4.66 – 4.39 (m, 2H), 4.31-4.19 (m, 1H), 4.17-4.03 (m, 2 H), 3.81 – 3.63 (m, 4 H), 3.47 –3.36 (m, 2 H), 3.31-3.23 (m, 2 H), 3.11-3.01 (m, 2 H), 2.94-2.78 (m, 2 H), 2.38-2.13 (m, 12H). Example 6. Exemplary synthesis of 1-[4'-chloro-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl] methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4- yl]azepan-4-one (Compound 21) and 2-(1-(4-chloro-2'-(((2R,7aS)-2-fluorotetrahydro- 1H- pyrrolizin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydrospiro[indene-1,7'-pyrano[4,3-d]pyrimidin]-4'- yl)azepan-4-yl)acetonitrile (Compound 19)
Figure imgf000225_0001
[00625] Step 1. Synthesis of 1-[4'-chloro-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl] methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4- yl]azepan-4-one (21). The mixture of 1-[4'-chloro-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl] methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4- yl]azepan-4-ol (6, 20.0 mg, 0.040 mmol) and DMP (23.43 mg, 0.060 mmol) was stirred at 25 °C for 30 min. The mixture was concentrated and purified by Prep-HPLC eluted with CH3CN in H2O (0.1 % FA) from 5.0% to 95% to afford 1-[4'-chloro-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro [5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4- yl]azepan-4-one;formic acid (21, 1.8 mg, 0.003 mmol, 8.0% yield) as sticky solid. LCMS calcld for C29H35ClFN4O3 (M+H)+ m/z =541.1, found: 541.1.1H NMR (400 MHz, CD3OD) δ 8.43 (s, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.07 (dd, J = 7.6, 1.9 Hz, 1H), 5.49 (d, J = 51.8 Hz, 1H), 4.73 (d, J = 14.6 Hz, 1H), 4.48 (d, J = 14.6 Hz, 1H), 4.42 (d, J = 11.6 Hz, 1H), 4.35 (d, J = 11.6 Hz, 1H), 3.95 (t, J = 6.1 Hz, 2H), 3.89 – 3.65 (m, 5H), 3.17 – 3.05 (m, 2H), 3.03 – 2.88 (m, 4H), 2.81 – 2.73 (m, 2H), 2.62 – 2.34 (m, 5H), 2.33 – 2.16 (m, 5H). [00626] Step 2. Synthesis of 2-(1-(4-chloro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydrospiro[indene-1,7'-pyrano[4,3-d]pyrimidin]-4'-yl)azepan- 4-ylidene)acetonitrile (19a). To a mixture of 1-[4'-chloro-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl] methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4- yl]azepan-4-one (21, 20.0 mg, 0.04 mmol) and 2-diethoxyphosphorylacetonitrile (6.55 mg, 0.04 mmol) in dried THF (1 mL) was added sodium hydride (1.77 mg, 0.07 mmol) at 25 °C under argon. The mixture was stirred at rt for 1 h. The mixture was diluted with EtOAc (10 mL), washed with water (5 mL) and brine (1 ml), dried over Na2SO4, concentrated. The crude product was purified by Prep-TLC to afford 2-[1-[4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4- yl]azepan-4-ylidene]acetonitrile (19a, 10 mg, 0.018 mmol, 48.0% yield) as yellow sticky solid. LCMS calcld for C31H35ClFN5O2 (M+H)+ m/z = 564.1, found: 564.1. [00627] Step 3. Preparation of 2-(1-(4-chloro-2'-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin- 7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydrospiro[indene-1,7'-pyrano[4,3-d]pyrimidin]-4'-yl)azepan- 4-yl)acetonitrile (19). The suspension of 2-[1-[4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl] methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4- yl]azepan-4-ylidene]acetonitrile (10.0 mg, 0.02 mmol) and Pd-C (0.19 mg, 0.0018mmol) in methanol (1 mL) was purged with H2 three times. The mixture was stirred under H2 (1 atm) at 25 °C for 16 h. The mixture was filtered and concentrated to afford a crude product which was purified by Prep-HPLC eluted with (eluted with CH3CN in H2O (0.1 % FA) from 5.0 % to 95 %) to obtain 2-[1-[4'-chloro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]azepan-4- yl]acetonitrile;formic acid (19, 2.24 mg, 0.0034 mmol, 18.9 % yield) as white sticky solid. LCMS calcld for C31H38ClFN5O2 (M+H)+ m/z = 566.2, found: 566.2.1H NMR (400 MHz, CD3OD) δ 8.47 (s, 1H), 7.41 – 7.08 (m, 3H), 5.45 (d, J = 51.1 Hz, 1H), 4.78 – 4.23 (m, 4H), 3.96 – 3.33 (m, 7H), 3.26 – 3.21 (m, 1H), 3.16 – 2.88 (m, 4H), 2.59 – 2.33 (m, 5H), 2.28 – 1.60 (m, 12H). Example 7. Exemplary synthesis of 4-(azepan-1-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,4'-tetralin]-6'- carbonitrile (Compound 20)
Figure imgf000226_0001
[00628] The solution of 4-(azepan-1-yl)-7'-bromo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-tetralin] (20a, prepared similarly to that of Ex.1, 30.mg, 0.05mmol), K2CO3 (21.24mg, 0.15mmol), Zn(CN)2 (18.05mg, 0.15mmol) and Xphos G3 Pd (4.69mg, 0.01mmol) in 1,4-Dioxane (1mL) and Water (0.2mL) was stirred at 100 °C under N2 for 6h. The reaction mixture was concentrated to get the crude product, which was then purified by prep-HPLC (eluted with CH3CN in H2O (0.1% FA) from 5% to 95%) to give 4-(azepan-1-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,4'-tetralin]-6'-carbonitrile;formic acid (20, 3.2mg, 0.0042mmol, 8.2% yield) as yellow solid. LCMS calcld for C31H38FN5O2 (M+H)+ m/z = 532.3; found: 532.3.1H NMR (400 MHz, CD3OD) δ 8.51 (s, 1H), 7.72-7.64 (m, 1H), 7.58-7.49 (m, 1H), 7.38-7.26 (m, 1H), 5.47-5.26 (m, 1H), 4.93-4.76 (m, 1H), 4.68-4.52 (m, 1H), 4.33-4.14 (m, 2H), 3.75-3.60 (m, 4H), 3.53-3.33 (m, 3H), 3.19-3.07 (m, 1H), 3.03-2.75 (m, 4H), 2.48-1.90 (m, 9H), 1.87-1.72 (m, 5H), 1.69-1.51 (m, 4H). [00629] Example 8. Exemplary synthesis of syn-1-[4'-chloro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'- indane]-4-yl]azepane-
Figure imgf000227_0001
[00630] To a mixture of 4'-chloro-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl] methoxy]-4-(2,3,6,7-tetrahydroazepin-1-yl)spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'- indane] (18, 50.0 mg, 0.1 mmol) in acetone (0.3 mL) and water (0.1 mL) were added K2OsO4.2H2O (70.17 mg, 0.19 mmol) and NMO (22.31 mg, 0.19 mmol) at 25 °C. Then the mixture was stirred at 40 °C for 16 h. The solution was quenched with Na2SO3 aqueous solution, extracted with EtOAc (3 ml), and concentrated. The residue was purified by prep-HPLC eluting with CH3CN in H2O ( 0.1 % TFA) from 5.0% to 95% to give syn-1-[4'-chloro-2-[[rac-(2R,8S)-2- fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3- d]pyrimidine-7,1'-indane]-4-yl]azepane-4,5-diol;2,2,2-trifluoroacetic acid (22, 4.71 mg, 0.0065 mmol, 6.8% yield) as a sticky solid. LCMS calcld for C31H37ClF4N4O6 (M+H)+ m/z =559.24, found: 559.5.1H NMR (400 MHz, CD3OD) δ 7.40-7.38 (dd, J =7.2, 0.8 Hz, 1H), 7.29-7.25 (t, J =7.6 Hz, 1H), 7.29 -7.23 (dd, J =7.6 Hz, 1.2 Hz, 1H), 5.67 (s, 2H), 5.60 (d, J = 52 Hz, 1H), 4.93 – 4.65 (m, 4H), 4.00 – 3.70 (m, 9H), 3.52 – 3.46 (m, 1H), 3.18 – 3.06 (m, 2H), 3.02 – 2.96 (m, 1H), 2.88 (m, 1 H), 2.75-2.65 (m, 1 H), 2.62 – 2.62 (m, 1 H), 2.50 – 2.12 (m, 8 H), 2.03 – 1.90 (m, 2 H). Example 9. Exemplary synthesis of (3R)-1-(4-chloro-2'-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydrospiro[indene-1,7'-pyrano[4,3-d]pyrimidin]-4'- yl)-3-methylpiperidin-3-ol (Compound 23)
Figure imgf000228_0001
[00631] Step 1. Synthesis of ethyl 4-chloro-6-((4-chloro-1-hydroxy-2,3-dihydro-1H-inden-1- yl)methyl)-2-(methylthio)pyrimidine-5-carboxylate (23a). To a solution of LiHMDS (1 M, 24.3 mL, 2.0 eq) in THF (10 mL) was added a solution of Ethyl 4-chloro-6-methyl-2- (methylthio)pyrimidine-5-carboxylate (3.0 g, 12.2 mmol, 1.0 eq) in THF (10 mL) at -60 °C. Then the reaction was stirred at -60 °C for 30 minutes. After 30 minutes, 4-chloro-2,3-dihydro- 1H-inden-1-one (2.03 g, 12.2 mmol, 1.0 eq) in THF (10 mL) was added to the mixture at -60 °C. Then the reaction was stirred at -60 °C for 1 hr. LCMS showed that the reaction was completed. The residue was poured into water (50 mL). The aqueous phase was extracted with EtOAc (20 mL * 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE: EtOAc = 80:1 to 30:1) to give ethyl 4-chloro-6-((4-chloro-1-hydroxy-2,3- dihydro-1H-inden-1-yl)methyl)-2-(methylthio)pyrimidine-5-carboxylate (23a) (3.5 g, 8.47 mmol, 69.64% yield) as a light-yellow oil.1H NMR (400 MHz, CDCl3) δ 7.24-7.25 (m, 1H), 7.17 (t, J =7.6 Hz, 1H), 7.06-7.08 (m, 1H), 5.29(s, 1H), 4.31-4.38 (m, 2H), 3.23-3.26 (m, 1H), 3.07-3.11 (m, 1H), 3.06-3.07 (m, 1H), 2.81-2.87 (m, 1H), 2.59 (s, 3H), 2.31-2.37 (m, 3H), 2.12- 2.20 (m, 1H), 1.33 (t, J =7.2 Hz, 3H). [00632] Step 2. Synthesis of 4-chloro-1-((6-chloro-5-(hydroxymethyl)-2- (methylthio)pyrimidin-4-yl)methyl)-2,3-dihydro-1H-inden-1-ol (23b). To a solution of compound 23a (3.4 g, 8.23 mmol, 1.0 eq) in DCM (35 mL) was added DIBAL-H (1 M, 24.68 Ml, 3.0 eq) at 0°C. The mixture was stirred at 0 °C for 1 hr. LCMS indicated the reaction was completed. The reaction mixture was quenched by water (50 mL) at 0°C, and then extracted with DCM (20 mL * 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE: EtOAc = 100:1 to 30:1) to give compound 23b (2.0 g, 5.39 mmol, 65.48% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) ^ 7.26-7.28 (m, 1H), 7.16 (t, J =8.0 Hz, 1H), 7.03-7.05 (m, 1H), 4.62-4.73 (m, , 2H), 3.34-3.38 (m, 1H), 3.13-3.16(m, 1H), 3.03-3.06 (m, 1H), 2.89-2.95 (m, 1H), 2.53 (s, 3H), 2.50-2.52 (m, 1H), 2.07-2.12 (m, 1H). [00633] Step 3. Synthesis of 4,4'-dichloro-2'-(methylthio)-2,3,5',8'-tetrahydrospiro[indene- 1,7'-pyrano[4,3-d]pyrimidine] (23c). To a solution of compound 23b (1.7 g, 4.58 mmol, 1.0 eq) in THF (20 mL) was added DIAD (1.39 g, 6.87 mmol, 1.34 mL, 1.5 eq) and PPh3 (1.8 g, 6.87 mmol, 1.5 eq) at 25 °C. Then the reaction was stirred at 25°C for 10 minutes. LC-MS showed the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (PE/EtOAc=100/1 to 80/1 to give compound 23c (1.07 g, 3.03 mmol, 66.15% yield) as off- white solid.1H NMR (400 MHz, CDCl3) δ 7.30-7.32 (m, 1H), 7.16 (t, J =8.0 Hz, 1H), 6.94-6.96 (m, 1H),4.72-4.76 (m, 1H), 4.56-4.60 (m, 1H), 3.13-3.19(m, H), 3.10(s, 2H), 2.95-2.96 (m, 1H), 2.58 (s, 3H), 2.36-2.40 (m, 1H), 2.11-2.16 (m, 1H). [00634] Step 4. Synthesis of (3R)-1-(4'-chloro-2-methylsulfanyl-spiro[5,8-dihydropyrano[4,3- d]pyrimidine-7,1'-indane]-4-yl)-3-methyl-piperidin-3-ol (23d). A solution of 4,4'-dichloro-2- methylsulfanyl-spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane] (80.mg, 0.23mmol) in DMF (0.3mL) was added (3R)-3-methylpiperidin-3-ol;hydrochloride (37.77mg, 0.25mmol) and DIPEA (87.8mg, 0.68mmol) at room temperature. The mixture was stirred at 100 °C for 1 h. The solution was diluted with EtOAc (5ml), then washed with water (2 ml x3), dried over Na2SO4 and concentrated. The residue was purified with prep-TLC (eluting with EtOAc ether in petroleum from 10 % to 90%) to give (3R)-1-(4'-chloro-2-methylsulfanyl-spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl)-3-methyl-piperidin-3-ol (23d, 80mg,0.185mmol, 81.8% yield). LCMS calcld for C22H26ClN3O2S (M+H)+ m/z = 432.98, found: 432.1. [00635] Step 5. Synthesis of 23e. A mixture of (3R)-1-(4'-chloro-2-methylsulfanyl-spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl)-3-methyl-piperidin-3-ol (23d, 80.mg, 0.19mmol) in THF (0.4mL) and Water (0.4mL) was added oxone (68.31mg, 0.22mmol) at 25 °C for 1 h. The reaction was quenched with Na2SO3 aqueous solution and diluted with EtOAc (3 ml). The organic layer was washed with water (3 ml x3), dried and concentrated to give 90 mg of 23e as a 5:1 ratio of mixture of sulfoxide and sulfone based on LCMS. LCMS calcld for C22H26ClN3O4S (M+H)+ m/z =448.98, 464.98, found: 448.1, 464.1. [00636] Step 6. Synthesis of (3R)-1-(4-chloro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydrospiro[indene-1,7'-pyrano[4,3-d]pyrimidin]-4'-yl)-3- methylpiperidin-3-ol (23). A mixture of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (177.69mg, 1.12mmol) in DMSO (0.3mL) was added NaH (44.64mg, 1.12mmol) at 25 °C for 0.5 h. Then a mixture sulfone and sulfoxide of 23e in DMSO (0.3mL) was added to the reaction at 25 °C and stirred for 1 h. Acetic acid was added dropwise until pH = 7. The crude mixture was purified by prep-HPLC (eluting with CH3CN (0.1% TFA )in H2O from 5 % to 95%) to give (3R)-1-[4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-3-methyl-piperidin-3- ol;2,2,2-trifluoroacetic acid (46.03mg,0.0695mmol, 31.13% yield) as a white solid. LCMS calcld for C29H36ClFN4O3 (M+H)+ m/z =543.07, found: 543.1.1H NMR (400 MHz, CD3OD) δ 7.38 (d, J=7.6 Hz, 1H), 7.28-7.20 (m, 2 H), 5.60 (d, J = 52 Hz, 1H), 4.99-4.96 (m, 1H), 4.78-4.50 (m, 4H), 4.35-4.278 (m, 1H), 4.01– 3.75 (m, 4H), 3.52-3.46 (m, 1H), 3.40-3.31 (m, 1 H), 3.25 – 3.07 (m, 3 H), 3.02– 2.96 (m, 1 H), 2.77-2.58 (m, 2 H), 2.49-2.26 (m, 6 H), 2.03-1.94 (m, 1 H), 1.82-1.71 (m, 3 H), 1.24 (s, 3H). [00637] Compound 24.9-[4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-1,3,9- triazaspiro[4.5]decane-2,4-dione.
Figure imgf000230_0001
[00638] Compound 24 was prepared similarly to that of Ex.9. LCMS calcld for C30H34ClFN6O4 (M+H)+ m/z = 597.09, found: 597.5.1H NMR (400 MHz, CD3OD) δ 7.34 – 7.27 (m, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.14 – 7.04 (m, 1H), 5.28 (d, J = 54.2 Hz, 1H), 4.75 – 4.58 (m, 1H), 4.53 – 4.40 (m, 1H), 4.23 – 4.03 (m, 2H), 4.01 – 3.66 (m, 2H), 3.43 – 3.35 (m, 1H), 3.26 – 3.05 (m, 5H), 3.04 – 2.89 (m, 4H), 2.43 – 2.05 (m, 6H), 2.00 – 1.78 (m, 6H). [00639] Compound 25.4-(azepan-1-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,4'-isochromane]
Figure imgf000230_0002
[00640] Compound 25 was prepared similarly to that of Ex.1 as a formic acid salt. LCMS (ESI)：m/z calcld for C29H37FN4O3(M+H)+: 509.2, found: 509.2.1H NMR (400 MHz, CD3OD) δ 7.41 – 7.36 (m, 1H), 7.30 – 7.18 (m, 2H), 7.09 (d, J = 7.5 Hz, 1H), 5.39 – 5.22 (m, 1H), 4.80 (m, 3H), 4.70 (d, J = 14.2 Hz, 1H), 4.64 – 4.52 (m, 1H), 4.23 – 4.07 (m, 2H), 3.96 – 3.86 (m, 2H), 3.68 – 3.61 (m, 4H), 3.30 – 3.17 (m, 2H), 3.08 – 2.99 (m, 1H), 2.96 – 2.89 (m, 2H), 2.37 – 1.77 (m, 10H), 1.65 – 1.54 (m, 4H). [00641] Example 10. Exemplary synthesis of 2'-amino-4-(azepan-1-yl)-2-[[rac-(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine- 7,4'-6,7-dihydro-5H-benzothiophene]-3'-carbonitrile (Compound 26)
Figure imgf000231_0001
[00642] Step 1. Synthesis of methyl 4-(azepan-1-yl)-2-chloro-6-[(2-ethoxy-1-hydroxy- cyclohex-2-en-1-yl)methyl]pyrimidine-5-carboxylate (26a). A mixture of methyl 4-(azepan-1- yl)-2-chloro-6-methyl-pyrimidine-5-carboxylate (1a, 1.0 g, 3.52mmol) and LDA (2.11mL, 4.23mmol) in THF (10mL) was stirred at -78 °C for 1 h. Then, a solution of 2-ethoxycyclohex-2- en-1-one (543mg, 3.88mmol) and CeCl3 (956mg, 3.88mmol), stirred for 4h in THF (5mL), was added at -78 °C. The mixture was stirred at -78 °C for 1 h. LCMS showed 42% of product and 35% of 1a remained. The mixture was quenched with aq. NH4Cl (5 mL) at -78 ºC, extracted with EtOAc (5 mL x 3), dried, and concentrated. The crude product was purified by flash chromatography (H2O:CH3CN = 90:10 to 50:50) to give methyl 4-(azepan-1-yl)-2-chloro-6-[(2- ethoxy-1-hydroxy-cyclohex-2-en-1-yl)methyl]pyrimidine-5-carboxylate (26a, 800mg,1.89mmol, 53.5% yield) was obtained as a yellow sticky oil. LCMS calcld for C21H30ClN3O4 (M+H)+ m/z = 424.2, found: 424.2. [00643] Step 2. Synthesis of 1-[[6-(azepan-1-yl)-2-chloro-5-(hydroxymethyl)pyrimidine-4- yl]methyl]-2-ethoxy-cyclohex-2-en-1-ol (26b). A suspension of LAH (177mg, 4.67mmol) and lithium chloride (198mg, 4.67mmol) in 2-Methyltetrahydrofuran (6mL) was stirred at room temperature for 20 min. Then methyl 4-(azepan-1-yl)-2-chloro-6-[(2-ethoxy-1-hydroxy- cyclohex-2-en-1-yl)methyl]pyrimidine-5-carboxylate (26a, 660.mg, 1.56mmol) was added at 0 °C portion wise. The mixture was stirred at 0 °C for 10 min. The mixture was quenched with NH4Cl (0.5 mL) at 25 °C, extracted with EtOAC (10 x 3 mL), dried over Na2SO4, concentrated. The crude product was purified by silica gel chromatography (eluted with EtOAc in PE from 10% to 30%) to give 1-[[6-(azepan-1-yl)-2-chloro-5-(hydroxymethyl)pyrimidin-4-yl]methyl]-2- ethoxy-cyclohex-2-en-1-ol (26b, 230mg,0.581mmol, 37.3% yield) as a yellow solid. LCMS calcld for C20H30ClN3O3 (M+H)+ m/z = 396.1, found: 396.1. [00644] Step 3. Synthesis of 4-(azepan-1-yl)-2-chloro-1'-ethoxy-spiro[5,8-dihydropyrano[4,3- d]pyrimidine-7,6'-cyclohexene] (26c). To a solution of 1-[[6-(azepan-1-yl)-2-chloro-5- (hydroxymethyl)pyrimidin-4-yl]methyl]-2-ethoxy-cyclohex-2-en-1-ol (26b, 230mg, 0.58mmol) in THF (2mL) was added n-Butyllithium (0.35mL, 0.87mmol) at -78 °C stirred for 0.5h. then the TSCl (166mg, 0.87mmol) in THF (2mL) was added at -78 °C and the mixture was warmed to - 10 °C stirred for 1 h under Ar. Then the temperature was cooled down to-78 °C and the second batch of n-Butyllithium (0.35mL, 0.87mmol) was added, after addition the reaction temperature was allowed to rise to 20 °C and stirred for 1.5 h. The mixture was quenched with NH4Cl (1 mL) at -78 °C, extracted with EtOAC (10 x 3 mL), dried over Na2SO4, concentrated. The crude product was purified by silica gel chromatography (eluted with EtOAc in PE from 1% to 20%) to give 4-(azepan-1-yl)-2-chloro-1'-ethoxy-spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,6'- cyclohexene] (26c, 130mg,0.344mmol, 59.2% yield) as a yellow solid. LCMS calcld for C20H28ClN3O2 (M+H)+ m/z = 378.1, found: 378.1. [00645] Step 4. Synthesis of 4-(azepan-1-yl)-1'-ethoxy-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,6'-cyclohexene] (26d). The mixture of NaH (31.8mg, 0.79mmol) and [(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methanol (126mg, 0.79mmol) in DMSO (1mL) was stirred at 0 °C for 0.5 h. Then a solution of 4-(azepan-1-yl)-2-chloro-1'-ethoxy-spiro[5,8-dihydropyrano[4,3- d]pyrimidine-7,6'-cyclohexene] (26c, 100.mg, 0.26mmol) in DMSO (0.5mL) was added at 0 °C and the mixture was stirred at 50 °C for 4 h. The mixture was quenched with H2O (10 mL) at 0 °C, extracted with EtOAC (5 x 3 mL), dried over Na2SO4, concentrated. The crude product was purified by silica gel chromatography (eluted with EtOAc in PE from 10% to 30%) to give 4-(azepan-1-yl)-1'-ethoxy-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,6'-cyclohexene] as a yellow solid (26d, 80mg,0.1598mmol, 60.387% yield) was obtained as yellow solid. LCMS calcld for C28H41FN4O3 (M+H)+ m/z = 501.2, found: 501.6. [00646] Step 5. Synthesis of 4-(azepan-1-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,2'-cyclohexane]- 1'-one (26e). The mixture of 4-(azepan-1-yl)-1'-ethoxy-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,6'-cyclohexene] (80.mg, 0.16mmol) and HCl/Dioxane (1.mL, 4.mmol) in Water (0.2mL) was stirred at 25 °C. the mixture was stirred at 25 °C for 10 min. After concentration, the crude product was purified by Prep-TLC (DCM:MeOH = 5:1). LCMS (ESI): m/z calcld for C26H37FN4O3 (M+H)+ m/z = 472.2, found: 473.2. [00647] Step 6. Synthesis of 2'-amino-4-(azepan-1-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,4'-6,7-dihydro- 5H-benzothiophene]-3'-carbonitrile (Compound 26). The mixture of 4-(azepan-1-yl)-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3- d]pyrimidine-7,2'-cyclohexane]-1'-one (26e, 68.mg, 0.14mmol) and propanedinitrile (9.5mg, 0.14mmol) and octathiocane (36.9mg, 0.14mmol) and morpholine (25mg, 0.29mmol) in Ethanol (0.5mL) was stirred at 65 °C, the mixture was stirred at 65 °C under argon for 7 h. The mixture was filtered and concentrated. The crude product was purified by Prep-HPLC (eluted with CH3CN in H2O (0.1 % TFA) from 5.0% to 95%) to give 2'-amino-4-(azepan-1-yl)-2-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3- d]pyrimidine-7,4'-6,7-dihydro-5H-benzothiophene]-3'-carbonitrile;2,2,2-trifluoroacetic acid (26, 2.9 mg, 0.003 mmol, 2.1 %yield) as a yellow sticky solid. LCMS (ESI): m/z calcld for C29H39FN6O2S (M+H)+ m/z =553.2, found: 553.2. [00648] Compound 23A and 23B. (3R)-1-[(7*)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 3-methyl-piperidin-3
Figure imgf000233_0001
[00649] Compound 23 was purified on an DAICELCHIRALCEL®AD (250*25 mm 10 mm) column on a Waters SFC 150 system (Mobile Phase A: Supercritical CO2, Mobile Phase B：IPA (+0.1% 7.0mol/l Ammonia in MeOH); A:B: 60:40; Flow: 70ml/min) to give faster eluting P1 (3R)-1-[(7*)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-3-methyl-piperidin-3- ol (23A) and slower eluting P2 (23B). Compound 23A: 1H NMR (400 MHz, CD3OD) δ 7.351- 7.332 (m, 1H), 7.235-7.916 (m, 1 H), 7.121-7.103 (m, 1H), 5.399-5.256 (m, 1 H), 4.749 (d, J=14 Hz, 1 H), 4.459 (d, J=14 Hz, 1 H), 4.228-4.119 (m, 2 H), 3.665–3.627(m, 1H), 3.422-3.349 (m, 2H), 3.284-3.231 (m, 4 H), 3.165 – 2.927 (m, 5 H), 2.443-1.867 (m, 10 H), 1.768-1.626 (m, 2H), 1.189 (s, 3 H). Compound 23B: 1H NMR (400 MHz, CD3OD) δ 7.227-7.207 (m, 1H), 7.116- 7.077 (m, 1 H), 7.041-7.022 (m, 1H), 5.291-5.155 (m, 1 H), 4.557-4.406 (m, 2 H), 4.150-4.017 (m, 2 H), 3.607-3.544 (m, 1 H), 3.380–3.347 (m, 1H), 3.297-3.255 (m, 1 H), 3.164-2.929 (m, 6 H), 2.884 – 2.802 (m, 3 H), 2.305-2.026 (m, 5H), 1.950-1.73(m, 5 H), 1.646-1.482 (m, 2 H), 1.090 (s, 3 H) . [00650] Compound 24A. (5*)-9-[(7*)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 1,3,9-triazaspiro[4.5]decane-2,4-dione
Figure imgf000234_0001
[00651] Compound 24 was purified on an DAICELCHIRALCEL®AD (250*25 mm 10 um) column on a Waters SFC 150 system (Mobile Phase A:Supercritical CO2, Mobile Phase B：IPA (+0.1% 7.0mol/l Ammonia in MeOH); A:B: 60:40; Flow: 70ml/min) to give 3 peaks and the fastest eluting P1 was assigned to compound 24A. Example 11. Exemplary synthesis of 5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (compound 27A) and 5-[(7R)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 27B)
Figure imgf000234_0002
[00652] Compound 27A was obtained from 27A-a similarly to that of compound 27B as a formic acid salt. The absolute configuration of 27A was assigned based on a small molecule crystal structure. LCMS calcld for C33H39ClFN7O4 (M+H)+ m/z = 636.3, found: 636.3.1H NMR (400 MHz, CD3OD) δ 8.51 (s, 1H), 7.38-7.20 (m, 2H), 7.08-7.00 (m, 1H), 6.53 (s, 1H), 5.46- 5.26 (m, 1H), 4.78-4.68 (m, 3H), 4.59-4.46 (m, 3H), 4.26-4.03 (m, 3H), 3.87-3.76 (m, 1H), 3.52- 3.31 (m, 7H), 3.18-2.88 (m, 8H), 2.46-1.90 (m, 10H). [00653] Compound 27B 5-[(7R)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000235_0001
[00654] Compound 23c was purified on an DAICELCHIRALCEL®AD (25*250 mm, 10 um) column on a Waters SFC 150 system (Mobile Phase A: Supercritical CO2, Mobile Phase B：IPA (+0.2% 7.0mol/l Ammonia in MeOH); A:B: 60:40; Flow: 100ml/min) to give 2 peaks and the fastest eluting P1 was assigned to compound 27A-a and the second one P2 was assigned as 27B- a.27B-a absolute configuration was assigned based on 27A-a single crystal structure. [00655] Step 1.27B-a (140.mg, 0.4mmol), N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide;hydrochloride (165.07mg, 0.79mmol) and DIEA (0.21mL, 1.19mmol) in DMF (2mL) was stirred at 100 °C for 2 h. The mixture was concentrated. The crude product was purified by flash chromatography (eluted with CH3CN in H2O from 5.0% to 95%) to get 5-[(7S)-4'-chloro-2-methylsulfanyl-spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'- indane]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide 27b (173 mg, 0.3295 mmol, 83.14% yield) as yellow solid. LCMS calcld for C26H29ClN6O2S (M+H)+ m/z = 525.1, found: 525.1.1H NMR (400 MHz, CDCl3) ^ 7.37-7.27 (m, 2H), 7.02 (d, J = 7.1 Hz, 1H), 6.49 (s, 1H), 4.69 – 4.39 (m, 7H), 3.78 – 3.65 (m, 1H), 3.35 (s, 3H), 3.23 – 3.11 (m, 3H), 3.09 (s, 3H), 2.99 – 2.92 (m, 1H), 2.52 (s, 3H), 2.41 – 2.13 (m, 4H). [00656] Step 2. To a solution 27b (170.mg, 0.32mmol) in THF (2mL) was added a solution of oxone (129.38mg, 0.42mmol) in Water (1mL) at 0 °C, then the mixture was stirred at 25 °C for 1 h. The mixture was added water (10 mL) and extracted with EtOAc (10 mL x 3), washed with a solution of Na2SO3 (5 mL), brine (5 ml), dried over Na2SO4, concentrated. The crude product was used directly for the next step. The crude product of N,N-dimethyl-5-[(7S)-4'-chloro-2- methylsulfinyl-spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide 27c (135mg,0.2495mmol, 77.07% yield) and N,N-dimethyl-5-[(7S)-4'-chloro-2-methylsulfonyl-spiro[5,8-dihydropyrano[4,3- d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide 27d (35 mg, 0.0628mmol, 19.41% yield) was obtained as yellow solid. LCMS calcld for 27c C26H29ClN6O3S (M+H)+ m/z = 541.1, found: 541.1, 21% of product 3-1. LCMS calcld for 27d C26H29ClN6O4S (M+H)+ m/z = 557.1, found: 557.1. [00657] Step 3. To a solution of^[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (88.27mg,0.55mmol) in^DMF (0.5mL) was added NaH (22.18mg, 0.55mmol) at 25 °C. The mixture was stirred at^25 °C for 15 min.^ A solution of^N, N-dimethyl-5-[(7S)-4'-chloro- 2-methylsulfinyl-spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide 27c (100.mg, 0.18mmol) and^N,N- dimethyl-5-[(7S)-4'-chloro-2-methylsulfonyl-spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'- indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide 27d (20.mg, 0.04mmol) in^DMF (0.5mL) was added the above solution at 25 °C.^ The mixture was stirred at^25 °C for 15 min. Acetic acid (0.03mL, 0.55mmol) was added the reaction mixture to quench the reaction. The crude product was purified by Prep-HPLC (eluted with CH3CN in H2O (0.1% FA) from 5.0% to 95%) to get 5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide;formic acid 27B (67.2 mg, 0.1052 mmol, 56.92% yield) was obtained as white solid. LCMS calcld for C33H39ClFN7O3 (M+H)+ m/z = 636.2, found: 636.2.1H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.04 (d, J = 7.4 Hz, 1H), 6.53 (s, 1H), 5.42 – 5.24 (m, 1H), 4.77 – 4.68 (m, 3H), 4.57 – 4.48 (m, 3H), 4.23 – 4.10 (m, 2H), 4.09 – 3.76 (m, 2H), 3.45 – 3.34 (m, 2H), 3.31 – 3.29 (m, 4H), 3.16 – 2.89 (m, 8H), 2.43 – 1.90 (m, 10H). Example 12. Exemplary synthesis of (7S)-4-(azepan-1-yl)-4'-chloro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-indane] (28A)
Figure imgf000236_0001
[00658] Step 1. Synthesis of methyl 4-(azepan-1-yl)-6-(((S)-1-(((R)-tert-butylsulfinyl)amino)- 4-chloro-2,3-dihydro-1H-inden-1-yl)methyl)-2-chloropyrimidine-5-carboxylate (28A-b). To a solution of LDA (1 M, 4.49 mL) in THF (3 mL) was added compound 1a (0.85 g, 3.00 mmol) at -65 °C. After the mixture was stirred at -65 °C for 30 minutes, (R)-N-(4-chloro-2,3-dihydro-1H- inden-1-ylidene)-2-methylpropane-2-sulfinamide (28A-a, Kobayashi, Jun-ichi; et al. Bioorganic & Medicinal Chemistry (2021), 30, 115903) (808 mg, 3.00 mmol) was added to the mixture at - 65 °C. The mixture was stirred at -65 °C for 1 hr. TLC indicated ~50% of 1a was remained and one major new spot with larger polarity was detected. The reaction mixture was poured into water (50 mL), the aqueous phase was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE: EtOAc = 80:1 to 10:1) to give methyl 4-(azepan-1-yl)-6-(((S)-1-(((R)-tert-butylsulfinyl)amino)- 4-chloro-2,3-dihydro-1H-inden-1-yl)methyl)-2-chloropyrimidine-5-carboxylate as a single diastereomer (28A-b, 0.65 g, 1.17 mmol, 39.20% yield) as an off-white solid.1H NMR (400 MHz, CDCl3) ^ 7.23-7.25 (m, 1H), 7.12-7.16 (m, 1H), 6.96-6.98 (m, 1H), 6.88 (s, 1H), 3.72 (s, 3H), 3.51-3.56 (m, 2H), 3.42-3.45 (m, 2H), 3.00-3.03 (m, 1H), 2.85-2.95 (m, 4H), 2.66-2.72 (m, 1H), 2.28-2.33 (m, 1H), 1.80(s, 4H), 1.49-1.56 (m, 4H), 1.29 (s, 9H). Chiral analysis of compound 28A-b (Chiralpak AD-3, 50×4.6mm I.D., 3um): 99.66%. The absolute configuration of 28A-b was assigned based on the single crystal structure of (R)-28A-d (HCl salt, not shown, prepared from (S)-28A-a). [00659] Step 2. Synthesis of (R)-N-((S)-1-((6-(azepan-1-yl)-2-chloro-5- (hydroxymethyl)pyrimidin-4-yl)methyl)-4-chloro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane- 2-sulfinamide (28A-c). To a solution of compound 28A-b (0.55 g, 994 umol) in DCM (10 mL) was added DIBAL-H (1 M, 2.98 mL) at 0 °C. Then the reaction was stirred at 0 °C for 1 hr. The reaction mixture was quenched by ice water (20 mL) at 25°C. The aqueous phase was extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, PE/EtOAc = 3:1) to give compound 28A-c (0.4 g, 761.13 umol, 76.60% yield) as off-white solid.1H NMR: (400 MHz, CDCl3) ^ 7.24 (s, 1H), 7.12-7.16 (m 1H), 7.01-7.03 (m 1H), 4.23-4.34 (m, 2H),3.70-3.74 (m, 4H), 3.08-3.19 (m, 3H), 2.93-2.95(m, 1H), 2.72-2.76 (m, 1H), 2.31-2.37 (m, 1H), 1.75-1.82 (m, 4H), 1.55-1.61 (m, 4H), 1.26 (s, 9H). [00660] Step 3. Synthesis of (S)-4'-(azepan-1-yl)-2',4-dichloro-2,3,5',8'-tetrahydro-6'H- spiro[indene-1,7'-pyrido[4,3-d]pyrimidine] (28A-d). To a solution of compound 28A-c (0.2 g, 4.58 mmol) in HCl/dioxane (4 M, 2 mL) at 0 °C. The mixture was stirred at 0 °C for 3 hrs. The reaction mixture was adjusted pH to 8 by NaHCO3 and extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. To a mixture of the residue in CHCl3 (1.5 mL) was added SOCl2 (154 mg, 1.29 mmol, 93.86 uL) at 0 °C, and the mixture was stirred at 50 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. To a mixture of the residue in THF (1.5 mL) was added NaOH (5M, 12mL) at 25 °C and the mixture was stirred at 25 °C for 1 hr. LC-MS showed the starting material was consumed completely. The mixture was extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (PE/EtOAc=1:1) to give compound 28A-d (0.1 g, 248 umol, 65% yield) as a light-yellow solid.1H NMR: (400 MHz, CDCl3) ^ 7.25-7.27 (m, 1H), 7.13-7.17 (m, 1H), 7.04-7.06 (m, 1H), 3.99-4.03 (m, 1H), 3.85-3.89 (m, 1H), 3.62-3.65 (m, 4H), 3.07-3.13 (m, 1H), 2.97-3.01 (m, 3H), 2.16-2.24 (m, 2H), 1.80 (s, 4H), 1.68 (m, 8H). [00661] Step 4. Synthesis of (S)-4'-(azepan-1-yl)-2',4-dichloro-6'-methyl-2,3,5',8'-tetrahydro- 6'H-spiro[indene-1,7'-pyrido[4,3-d]pyrimidine] (28A-e). To a solution of compound 28A-d (95 mg, 236 umol) in DMF (1 mL) was added NaH (9.42 mg, 235.53 umol, 60% purity) and iodomethane (33.4 mg, 236 umol, 14.7 uL) at 25 °C. Then the reaction was stirred at 25 °C for 2 hrs. LC-MS showed the starting material was consumed completely. The reaction mixture was quenched by water (5 mL), and then extracted with EtOAc (3 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EtOAc=1:1) to give compound 28A-e (40 mg, 96 umol, 41% yield) as light-yellow solid. [00662] Step 5. Synthesis of (7S)-4-(azepan-1-yl)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- indane] (28A). To a solution of compound 28A-e (17 mg, 40.73 umol) and((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (12.97 mg, 81.46 umol) in toluene (0.2 mL) was added Cs2CO3 (39.81 mg, 122.19 umol) and RuPhos Pd G3 (3.41 mg, 4.07 umol) at 20 °C. Then the reaction was stirred at 100 °C for 5 hrs. LC-MS showed the starting material was consumed completely. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [water(NH4HCO3)-ACN]; B%: 60%-80%,8min) to give compound 28A (1.4 mg, 2.59 umol, 6.4% yield) as an off-white solid.1H NMR (400 MHz, CD3OD) ^ 7.29-7.3 (m, 1H), 7.26-7.28 (m, 1H), 7.17-7.24 (m, 1H), 5.21-5.34 (m, 1H), 4.14-4.17 (m, 1H),4.03-4.06 (m, 1H), 3.72-3.81 (m, 6H), 3.15-3.21 (m, 3H), 2.98 (m, 3H), 2.80-2.88 (m, 2H), 2.37-2.45 (m, 1H), 2.25-2.30 (m, 1H), 2.17 (m, 3H), 2.15-2.25 (m, 1H), 2.10-2.05 (m, 1H), 1.88 (m, 2H), 1.64-1.65 (m, 6H), 1.28 (m, 4H). [00663] Example 13. Exemplary synthesis of [1-[4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 3-piperidyl]cyanamide (29)
Figure imgf000239_0001
[00664] To the mixture of 1-[4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]piperidin-3-amine (29a, prepared similarly to that of Ex.11) (60 mg, 0.11mmol) and Et3N (0.08mL, 0.57mmol) in DCM (0.4mL) at 0 °C was added carbononitridic bromide (13 mg, 0.12mmol) in DCM (0.2mL) and stirred at 0 °C for 0.5h. The mixture was taken into water (10 mL), which was extracted with DCM (3 x 5 mL). The organic layers were washed with brine (10 ml), dried over Na2SO4, and concentrated. The crude was purified by prep-HPLC (eluted with CH3CN in H2O (0.1 % FA) from 5.0% to 95%) to give [1-[4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-3- piperidyl]cyanamide; formic acid (29, 15.24 mg,0.0264 mmol, 23.23% yield) as a white solid. LCMS calcld for C29H34ClFN6O2 (M+H)+ m/z = 553.1, found: 553.1.1H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 7.32 (dd, J = 7.5, 3.1 Hz, 1H), 7.20 (dd, J = 14.7, 7.5 Hz, 1H), 7.13 – 7.09 (m, 1H), 5.44 – 5.23 (m, 1H), 4.78 – 4.69 (m, 1H), 4.61 – 4.53 (m, 2H), 4.52 – 4.39 (m, 1H), 4.28 – 4.15 (m, 2H), 4.02 – 3.95 (m, 1H), 3.57 – 3.46 (m, 1H), 3.42 – 3.34 (m, 2H), 3.25 – 2.93 (m, 7H), 2.45 – 1.83 (m, 10H), 1.69 – 1.54 (m, 2H). [00665] Compound 30.9-[6'-hydroxy-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 1,3,9-triazaspiro[4.5]decane-2,4-dione.
Figure imgf000239_0002
[00666] Compound 30 was prepared similarly to that of Ex.9 as a TFA salt. LCMS calcld for C30H35FN6O5 (M+H)+ m/z = 579.3, found: 579.1.1H NMR (400 MHz, CD3OD) δ 7.15 – 7.08 (m, 1H), 6.80 – 6.72 (m, 1H), 6.62 – 6.56 (m, 1H), 5.66 – 5.48 (m, 1H), 4.70 – 4.51 (m, 4H), 4.26 – 3.98 (m, 2H), 3.94 – 3.84 (m, 2H), 3.78 – 3.66 (m, 1H), 3.53 – 3.37 (m, 3H), 3.04 – 2.97 (m, 2H), 2.82 – 2.54 (m, 3H), 2.46 – 2.28 (m, 4H), 2.25 – 2.08 (m, 4H), 2.00 – 1.79 (m, 3H). [00667] Compound 31. N-methoxy-5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000240_0001
[00668] Compound 31 was prepared from 27B-a similarly to that of Ex.11 as a formic acid salt. LCMS calcld for C32H37ClFN7O4 (M+H)+ m/z = 638.2 found:638.2.1H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 7.37 – 7.26 (m, 2H), 7.02 (d, J = 7.3 Hz, 1H), 6.61 (s, 1H), 5.39 – 5.20 (m, 1H), 4.76 – 4.67 (m, 3H), 4.56 – 4.46 (m, 3H), 4.10 (d, J = 17.1 Hz, 2H), 3.78 (s, 3H), 3.26 – 3.19 (m, 2H), 3.16 – 2.80 (m, 6H), 2.49 – 1.78 (m, 12H) [00669] Compound 32. N-methoxy-5-[4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000240_0002
[00670] Compound 32 was prepared similarly to that of Ex.9 as a TFA salt. LCMS calcld for C33H40FN7O4 (M+H)+ m/z = 618.3, found: 618.2.1H NMR (400 MHz, CD3OD) δ 7.14 (d, J = 8.3 Hz, 1H), 6.77 (dd, J = 8.1, 2.4 Hz, 1H), 6.64 (d, J = 1.6 Hz, 1H), 6.54 (t, J = 2.6 Hz, 1H), 5.69 – 5.51 (m, 1H), 4.96 – 4.90 (m, 2H), 4.86 – 4.74 (m, 2H), 4.68 – 4.57 (m, 1H), 4.55 – 4.46 (m, 3H), 4.07 – 3.83 (m, 5H), 3.55 – 3.42 (m, 1H), 3.38 – 3.35 (m, 3H), 3.15 – 2.90 (m, 6H), 2.82 – 2.57 (m, 3H), 2.52 – 2.31 (m, 4H), 2.28 – 2.04 (m, 4H). [00671] Compound 33. (3aR,6aS)-5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 3a,4,6,6a-tetrahydropyrrolo[3,4-c]pyrrole-1,3-dione
Figure imgf000241_0001
[00672] Compound 33 was prepared from 27B-a similarly to that of Ex.11 as a TFA salt. LCMS calcld for C29H31ClFN5O4 (M+H)+ m/z = 568.2, found: 568.1.1H NMR (400 MHz, CD3OD) δ 7.36 (dd, J = 7.9, 0.7 Hz, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 5.69 – 5.50 (m, 1H), 4.86 – 4.81 (m, 1H), 4.69 – 4.52 (m, 3H), 4.34 (d, J = 12.9 Hz, 1H), 4.22 (d, J = 12.9 Hz, 1H), 4.03 – 3.87 (m, 3H), 3.83 – 3.70 (m, 2H), 3.58 – 3.45 (m, 3H), 3.19 – 3.09 (m, 1H), 3.05 – 2.91 (m, 3H), 2.75 – 2.57 (m, 2H), 2.48 – 2.31 (m, 4H), 2.27 – 2.17 (m, 2H). [00673] Compound 34. [5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-pyrrolidin-1-yl-methanone
Figure imgf000241_0002
[00674] Compound 34 was prepared from 27B-a similarly to that of Ex.11 as a formic acid salt. LCMS calcld for C30H34ClFN6O4 (M+H)+ m/z = 597.09, found: 597.5.1H NMR (400 MHz, CD3OD) ^ 7.34 -m7.27 (m, 1H), (t, J = 7.7 Hz, 1H), 7.14 – 7.04 (m, 1H), 5.28 (d, J = 54.2 Hz, 1H), 4.75 – 4.58 (m, 2H), 4.53 – 4.40 (m, 2H), 4.23 – 4.03 (m, 2H), 4.01 – 3.66 (m, 2H), 3.43 – 3.35 (m, 1H), 3.26 – 3.05 (m, 5H), 3.04 – 2.89 (m, 4H), 2.43 – 2.05 (m, 6H), 2.00 – 1.78 (m, 6H). [00675] Compound 35.5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- N-isopropyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000242_0001
[00676] Compound 35 was prepared from 27B-a similarly to that of Ex.11 as a formic acid salt. LCMS calcld for C30H34ClFN6O4 (M+H)+ m/z = 597.09, found: 597.5.1H NMR (400 MHz, CD3OD) ^ 7.34 - 7.27 (m, 1H), 7,20 (t, J = 7.7 Hz, 1H), 7.14 – 7.04 (m, 1H), 5.28 (d, J = 54.2 Hz, 1H), 4.75 – 4.58 (m, 1H), 4.53 – 4.40 (m, 1H), 4.23 – 4.03 (m, 3H), 4.01 – 3.66 (m, 3H), 3.43 – 3.35 (m, 1H), 3.26 – 3.05 (m, 5H), 3.04 – 2.89 (m, 4H), 2.43 – 2.05 (m, 6H), 2.00 – 1.78 (m, 6H). [00677] Compound 36.3-chloro-5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000242_0002
[00678] Compound 36 was prepared from 27B-a similarly to that of Ex.11 as a formic acid salt. LCMS calcld for C33H38Cl2FN7O3 (M+H)+ m/z = 670.5, found: 670.5.1H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 7.32 (d, J = 7.1 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 7.1 Hz, 1H), 5.40 – 5.20 (m, 1H), 4.82 – 4.76 (m, 3H), 4.59 (d, J = 14.3 Hz, 1H), 4.46 – 4.39 (m, 2H), 4.14 – 4.05 (m, 2H), 3.90 – 3.80 (m, 2H), 3.26 – 3.20 (m, 2H), 3.15 – 3.04 (m, 8H), 3.01 – 2.96 (m, 2H), 2.47 – 1.77 (m, 12H). [00679] Compound 37.5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- N-hydroxy-N-methyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000242_0003
[00680] Compound 37 was prepared from 27B-a similarly to that of Ex.11 as a formic acid salt. LCMS calcld for C32H38ClFN7O4 (M+H)+ m/z = 639.1, found: 638.3.1H NMR (400 MHz, CD3OD) δ 7.36 (d, J = 7.9 Hz, 1H), 7.26 (s, 1H), 7.08 (d, J = 7.5 Hz, 1H), 6.82 (s, 1H), 5.30 (d, J = 52.8 Hz, 1H), 4.81 – 4.68 (m, 3H), 4.55 (d, J = 13.8 Hz, 3H), 4.13 (d, J = 10.2 Hz, 1H), 4.03 (s, 2H), 3.87 (s, 1H), 3.44 (s, 2H), 3.29 (s, 2H), 3.22 (s, 1H), 3.17 – 2.91 (m, 5H), 2.40 (dd, J = 10.5, 7.1 Hz, 1H), 2.31 – 2.07 (m, 6H), 1.98 (dd, J = 17.8, 6.1 Hz, 2H), 1.88 (s, 1H). [00681] Compound 38. morpholino-[5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]methanone;2,2,2-trifluoroacetic acid
Figure imgf000243_0001
[00682] Compound 38 was prepared from 27B-a similarly to that of Ex.11 as a TFA salt. LCMS calcld for C35H41ClFN7O4 (M+H)+ m/z =678.2, found: 678.2.1H NMR (400 MHz, CD3OD) δ 7.37 (d, J = 7.6 Hz, 1H), 7.29-7.25 (m, 1H), 7.11 (d, J = 6.4 Hz, 1H), 6.66 (s, 1H), 5.58 (d, J = 51.6 Hz, 1H), 5.01-4.99 (m, 3H), 4.63-4.52 (m, 5H), 4.12-4.01 (m, 3H), 3.94-3.83 (m, 4H), 3.77–3.68 (m, 6H), 3.47-3.45 (m, 1H), 3.13-3.94 (m, 4H), 2.70 – 2.14 (m, 10H) [00683] Example 14.5-[7'-hydroxy-6-methyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]- N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 39)
Figure imgf000244_0001
[00684] Step 1. To a solution of 7-hydroxytetralin-1-one (30000.mg, 184.97mmol) in DMF (200mL) was added K2CO3 (51128.92mg, 369.94mmol) at rt, then BnBr (34798.63mg, 203.47mmol) was added. The mixture was stirred at rt for 16h. Then the mixture was extracted with EtOAc/H2O. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The obtained solid is triturated in MeOH and then filtered. The filtrate was purified by flash column chromatography (silica gel, eluting with EtOAc in PE) to afford 7- benzyloxytetralin-1-one (39a) (41760 mg, 166 mmol, 89.48 %yield) as a yellow solid. LCMS calculated for C17H17O2 (M+H)+ m/z =253.1; found:253.2.1H NMR (400 MHz, DMSO) δ 7.18 – 7.49 (m, 8H), 5.14 (s, 2H), 2.87 (t, J = 5.6 Hz, 2H), 2.57 (t, J = 6.4 Hz, 2H), 1.96 – 2.07 (m, 2H). [00685] Step 2.7-benzyloxytetralin-1-one (39a) (4320.mg, 17.12mmol), (S)-2- methylpropane-2-sulfinamide (2905.23mg, 23.97mmol) and Ti(IV) ethoxide (10.mL, 51.37mmol) were mixed and stirred under argon at rt. The reaction vessel was placed into the microwave reactor and heated to 100 °C for 120 min. The mixture was quenched with potassium sodium tartrate tetrahydrate (aq, 250 mL), filtered, extract with EtOAc and purified by flash column chromatography (silica gel, eluting with 10% to 30% EtOAc/PE) to afford (NE,S)-N-(7- benzyloxytetralin-1-ylidene)-2-methyl-propane-2-sulfinamide (39b) (3300 mg, 9.28 mmol, 54.22 %yield) as a brown oil. LCMS calculated for C21H26NO2S (M+H)+ m/z =356.17; found: 356.3. [00686] Step 3. To a solution of EtOAc (2478.55mg, 28.13mmol)in THF (16mL) was added LDA (5.60mL, 11.25mmol) portion wise at -70 °C under Ar, the mixture was stirred at -70 °C for 1h, then another 1 equiv LDA was added and the reaction stirred for an additional 1 hr at -70 °C, and (NE,S)-N-(7-benzyloxytetralin-1-ylidene)-2-methyl-propane-2-sulfinamide (39b) (2000.mg, 5.63mmol) in THF (8mL) was added drop wise at -70 °C . The resulting mixture was stirred at -70 °C for 2h, The reaction was heated naturally and overnight. The reaction mixture was quenched with NH4Cl(aq.) at -70 °C, and then extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 6% MeOH/DCM) to afford ethyl 2-[7-benzyloxy- 1-[[(S)-tert-butylsulfinyl]amino]tetralin-1-yl]acetate (39c) (1200 mg, 2.71 mmol, 48.08 %yield). LCMS calculated for C25H33NNaO4S+ (M+Na)+ m/z =466.20; found: 466.4. [00687] Step 4. The mixture of ethyl 2-[7-benzyloxy-1-[[(S)-tert-butylsulfinyl]amino]tetralin- 1-yl]acetate (39c) (1200.mg, 2.71mmol) and HCl in dioxane (5.mL, 20.mmol) in Ethanol (10mL) was stirred at rt for 1 h. The reaction mixture was concentrated to afford crude ethyl 2- (1-amino-7-benzyloxy-tetralin-1-yl)acetate (39d) (918mg,2.7045mmol, 100% yield). LCMS calculated for C21H26NO3 (M+H)+ m/z =340.19; found: 323.4. [00688] Step 5. A mixture of ethyl 2-(1-amino-7-benzyloxy-tetralin-1-yl)acetate (39d) (918.mg, 2.7mmol), ethyl prop-2-enoate (812.33mg, 8.11mmol), TEA (1.13mL, 8.11mmol) and CuO (43.03mg, 0.54mmol) was dissolved in Ethanol (9mL). The vial was sealed, and this mixture was then stirred for 16h at 85 °C. The crude reaction mixture was filtered and purified by Prep-HPLC (FA) to afford ethyl 3-[[7-benzyloxy-1-(2-ethoxy-2-oxo-ethyl)tetralin-1- yl]amino]propanoate (39e) (620mg,1.4106mmol, 52.2% yield) as a colorless oil. LCMS calculated for C26H34NO5 (M+H)+ m/z =440.24; found: 440.5. [00689] Step 6. To a solution of ethyl 3-[[7-benzyloxy-1-(2-ethoxy-2-oxo-ethyl)tetralin-1- yl]amino]propanoate (39e) (620.mg, 1.41mmol) in Ethanol (6mL) was added paraformaldehyde (253.9mg, 8.46mmol). Then the mixture was stirred at rt for 1h under N2, and NaBH3CN (265.92mg, 4.23mmol) was added. The resulting mixture was stirred at rt overnight. The reaction mixture was quenched with water, and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 25% EtOAc/PE) to afford ethyl 3-[[7-benzyloxy-1-(2-ethoxy-2-oxo- ethyl)tetralin-1-yl]-methyl-amino]propanoate (39f) (540mg,1.1906mmol, 84.4% yield) as a colorless oil. LCMS calculated for C27H36NO5 (M+H)+ m/z =454.26; found: 454.5. [00690] Step 7. To a solution of ethyl 3-[[7-benzyloxy-1-(2-ethoxy-2-oxo-ethyl)tetralin-1-yl]- methyl-amino]propanoate (39f) (440.mg, 0.97mmol) in THF (6mL) was added LIHMDS (2.91mL, 2.91mmol) portion wise at -70 °C under N2. Then the mixture was stirred at -70 °C for 1h. The reaction mixture was quenched with aqueous NH4Cl at -70 °C. The mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 15% EtOAc/PE) to afford ethyl 7'- benzyloxy-1-methyl-4-oxo-spiro[piperidine-6,1'-tetralin]-3-carboxylate (39g) (154mg,0.3779mmol, 39.0% yield) as a colorless oil. LCMS calculated for C25H30NO4 (M+H)+ m/z =408.22; found: 408.4. [00691] Step 8. To a solution of ethyl 7'-benzyloxy-1-methyl-4-oxo-spiro[piperidine-6,1'- tetralin]-3-carboxylate (39g) (279.mg, 0.68mmol) in ethanol (3mL) was added thiourea (67.75mg, 0.89mmol) and ethoxysodium (139.77mg, 2.05mmol). Then the mixture was stirred at 80 °C for 16h. The reaction mixture was concentrated, diluted with EtOAc.1M HCl was added to adjust pH=6. The mixture was washed with water and brine, dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 2% to 8% MeOH/DCM) to afford 7'-benzyloxy-6-methyl-2-sulfanyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]- 4-ol (39h) (250mg,0.5959mmol, 87.0% yield) as a yellow gel. LCMS calculated for C24H26N3O2S (M+H)+ m/z =420.18; found: 420.4. [00692] Step 9. To a solution of 7'-benzyloxy-6-methyl-2-sulfanyl-spiro[5,8- dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-4-ol (39h) (250.mg, 0.6mmol) in water (5mL) was added 2-chloroacetic acid (506.81mg, 5.36mmol). Then the mixture was stirred at 100 °C overnight under N2. The mixture was filtered. The pH of the aqueous layer was adjusted to 8 by adding an aqueous solution of NaHCO3 aqueous. The resulting precipitate was filtered, and dried in vacuo to afford 7'-benzyloxy-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-2,4-diol (39i) (224mg,0.5552mmol, 93.2% yield) as a white solid. LCMS calculated for C24H26N3O3 (M+H)+ m/z =404.20; found: 404.4. [00693] Step 10. The mixture of 7'-benzyloxy-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-tetralin]-2,4-diol (39i) (224.mg, 0.56mmol) in POCl3 (3.mL, 32.19mmol) was stirred at 100°C for 16 h. The reaction mixture was concentrated, extracted with EtOAc, washed with brine (10 mL), dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 30% EtOAc/PE) to afford 7'-benzyloxy-2,4- dichloro-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin] (39j) (28mg,0.064mmol, 11% yield) as a white solid. LCMS calculated for C24H24Cl2N3O (M+H)+ m/z =440.13, 442.13; found: 440.4, 442.4. [00694] Step 11. The mixture of 7'-benzyloxy-2,4-dichloro-6-methyl-spiro[5,8- dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin] (39j) (28.mg, 0.06mmol), N,N-dimethyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide;hydrochloride (18.67mg, 0.08mmol) and DIEA (16.44mg, 0.13mmol) in DMF (1mL) was stirred at rt for 24 h. The reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 3% to 7% MeOH/DCM) to afford 5-(7'-benzyloxy-2-chloro-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-tetralin]-4-yl)-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine- 2-carboxamide (39k) (25mg,0.041mmol, 64% yield) as a white solid. LCMS calculated for C34H39ClN7O2 (M+H)+ m/z =612.29; found: 612.4. [00695] Step 12. The mixture of 5-(7'-benzyloxy-2-chloro-6-methyl-spiro[5,8- dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-4-yl)-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (39k) (25.mg, 0.04mmol), [(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (8.45mg, 0.05mmol),Cs2CO3 (33.28mg, 0.1mmol), Pd2dba3 (3.74mg, 0.mmol) and RuPhos (3.81mg, 0.01mmol) in toluene (1.5mL) was stirred at 110°C for 10 h under N2. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The mixture was purified by flash column chromatography (silica gel, eluting with 0% to 10% MeOH/DCM) to afford 5-[7'-benzyloxy-6- methyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8- dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (39l) (25mg,0.034mmol, 83% yield) as a white solid. LCMS calculated for C42H52FN8O3 (M+H)+ m/z =735.42; found: 735.8. [00696] Step 13. The mixture of 5-[7'-benzyloxy-6-methyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]- N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (39l) (25.mg, 0.03mmol) and Pd/C (7.82mg, 0.01mmol) in MeOH (1mL) was stirred at rt for 2 h under H2. The reaction mixture was filtered, concentrated and purified by prep-HPLC(0.1% NH4HCO3) to afford 5-[7'-hydroxy-6-methyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 39) (7.84mg,0.0122mmol, 35.7% yield) as a white solid. LCMS calculated for C35H46FN8O3 (M+H)+ m/z =645.37; found: 645.7.1H NMR (400 MHz, CD3OD) δ 6.92 (dd, J = 7.6, 5.6 Hz, 2H), 6.58 – 6.64 (m, 2H), 5.26 (d, J = 54.4 Hz, 1H), 4.79 – 4.89 (m, 2H), 4.42 – 4.59 (m, 2H), 3.92 –4.14 (m, 4H), 3.76 (dd, J = 34.0, 14.8 Hz, 2H), 3.32 (s, 3H), 3.14 – 3.27 (m, 3H), 3.06 (s, 3H), 2.87 – 3.03 (m, 3H), 2.65 (dd, J = 9.6, 4.0 Hz, 2H), 2.12 – 2.36 (m, 3H), 2.14 (s, 3H), 1.67 – 2.10 (m, 9H). [00697] Compound 39A and 39B.5-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7'-hydroxy-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-tetralin]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine- 2-carboxamide (39A) and 5-[(7R)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-7'-hydroxy-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]- N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (39B)
Figure imgf000248_0001
[00698] Compound 39 was purified on an DAICELCHIRALCEL®AD (250*25 mm 10 um) column on a Waters SFC 150 system (Mobile Phase A: Supercritical CO2, Mobile Phase B: MeOH (0.2%NH3(7M in MeOH)); A:B: 65:35; Flow: 100ml/min) to give faster eluting P1 (39A) and slower eluting P2 (39B). [00699] Compound 40.5-[8'-chloro-7'-hydroxy-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-tetralin]-4- yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide.
Figure imgf000248_0002
[00700] Compound 40 was prepared similarly to that of Ex.9 as a white solid. LCMS calculated for C34H42ClFN7O4 (M+H)+ m/z =666.3; found: 666.5/668.5.1H NMR (400 MHz, CD3OD) δ 6.94 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 5.32 (d, J = 54.4 Hz, 1H), 5.02 (d, J = 14.0 Hz, 1H), 4.90 (s, 2H), 4.69 (d, J = 14.4 Hz, 1H), 4.44 – 4.53 (m, 2H), 4.00 – 4.20 (m, 3H), 3.84 – 3.92 (m, 1H), 3.58 (d, J = 18.0 Hz, 1H), 3.34 (d, J = 18.0 Hz, 1H), 3.27 (s, 3H), 3.06 (s, 3H), 3.01 – 3.11 (m, 1H), 2.75 – 2.83 (m, 3H), 1.87 – 2.40 (m, 13H), 1.68 – 1.80 (m, 1H). [00701] Example 15. Exemplary synthesis of 5-[6'-(difluoromethoxy)-2-[[rac-(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine- 7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (41)
Figure imgf000249_0001
[00702] To a solution of 5-[6'-hydroxy-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide;2,2,2- trifluoroacetic acid (32) (15.mg, 0.02mmol) in MeCN (0.3mL) were added 1- [[bromo(difluoro)methyl]-ethoxy-phosphoryl]oxyethane (8.21mg, 0.03mmol) and KF (2.38mg, 0.04mmol) at 25 °C. The mixture was stirred at 25 °C for 12 h. The crude product was purified by Prep-HPLC (eluted with CH3CN in H2O (0.1 % TFA) from 5.0% to 95%) to afford 5-[6'- (difluoromethoxy)-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide;2,2,2-trifluoroacetic acid (41) (5.4 mg , 0.0055 mmol, 27 % yield) as white solid. LCMS calcld for C34H40F3N7O4 (M+H)+ m/z = 668.3, found: 668.2.1H NMR (400 MHz, CD3OD) δ 7.59-7.26 (m, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.75 (dd, J = 8.1, 2.4 Hz, 1H), 6.61 (s, 1H), 6.54 (s, 1H), 5.78 – 5.57 (m, 1H), 4.81 – 4.69 (m, 4H), 4.67 – 4.23 (m, 6H), 4.05 – 3.89 (m, 3H), 3.33 (s, 3H), 3.12 – 2.88 (m, 8H), 2.81 – 2.68 (m, 2H), 2.64 – 2.47 (m, 3H), 2.45 – 2.29 (m, 2H), 2.21 – 2.06 (m, 3H). [00703] Compound 42.5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- N,N,3-trimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000249_0002
[00704] Compound 42 was prepared from 27B-a similarly to that of Ex.11 as a TFA salt. LCMS calcld for C34H42ClFN7O3 (M+H)+ m/z =650.3, found: 650.3.1H NMR (400 MHz, CD3OD) δ 7.36 (dd, J = 7.9, 0.8 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 5.60 (d, J = 50.7 Hz, 1H), 4.87 (s, 2H), 4.72 (dd, J = 86.4, 14.4 Hz, 2H), 4.52 (s, 2H), 4.41 (dd, J = 6.6, 3.3 Hz, 2H), 4.00 – 3.83 (m, 5H), 3.47 (td, J = 11.1, 5.4 Hz, 1H), 3.21 – 2.91 (m, 10H), 2.85 – 2.53 (m, 2H), 2.49 – 2.09 (m, 11H). [00705] Compound 43.5-[5'-chloro-7'-hydroxy-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-tetralin]-4- yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (43)
Figure imgf000250_0001
[00706] Compound 43 was prepared similarly to that of Ex.9 as a white solid. LCMS calculated for C34H42ClFN7O4 (M+H)+ m/z =666.3; found:666.3/668.3.1H NMR (400 MHz, CD3OD) δ 6.80 (d, J = 2.4 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 6.55 (d, J = 2.0 Hz, 1H), 5.37 (d, J = 53.6 Hz, 1H), 4.77 – 4.80 (m, 2H), 4.60 – 4.61 (m, 1H), 4.55 – 4.57 (m, 1H), 4.45 – 4.51 (m, 2H), 4.14 – 4.26 (m, 2H), 3.91 – 3.99 (m, 2H), 3.35 – 3.51 (m, 3H), 3.30 (s, 3H), 3.10 – 3.19 (m, 1H), 3.07 (s, 3H), 2.99 (d, J = 18.0 Hz, 1H), 2.91 (d, J = 18.0 Hz, 1H), 2.66 – 2.83 (m, 2H), 2.26 – 2.45 (m, 2H), 2.16 – 2.25 (m, 1H), 2.05 – 2.15 (m, 5H), 1.90 – 2.03 (m, 3H), 1.70 – 1.84 (m, 1H). [00707] Compound 44. [(3R)-1-[(7S)-4'-chloro-2-[[(2R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4- yl]azepan-3-yl]cyanamide
Figure imgf000250_0002
[00708] Compound 44 was prepared similarly to that of Ex.11 and Ex.13 as a TFA salt. LCMS calcld for C30H36ClFN6O2 (M+H)+ m/z = 567.1 , found 567.2. [00709] Compound 45. [3-chloro-5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-morpholino-methanone
Figure imgf000251_0001
[00710] Compound 45 was prepared from 27B-a similar to that of Ex.11. LCMS calcld for C35H41Cl2FN7O4 (M+H)+ m/z =712.3, found: 712.2.1H NMR (400 MHz, CD3OD) δ 7.36 (d, J = 7.4 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 5.60 (d, J = 51.9 Hz, 1H), 4.94 – 4.74 (m, 3H), 4.62 (d, J = 14.5 Hz, 1H), 4.45 – 4.44 (m, 2H), 4.42 – 4.31 (m, 2H), 4.03 – 3.81 (m, 6H), 3.77 (s, 3H), 3.69 (s, 3H), 3.46 (td, J = 11.1, 5.9 Hz, 1H), 3.21 – 2.92 (m, 4H), 2.81 – 2.53 (m, 2H), 2.52 – 2.12 (m, 9H). [00711] Compound 46A and 46B. [(3R)-1-[(7*)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 3-methyl-3-piperidyl]cyanamide;2,2,2-trifluoroacetic acid
Figure imgf000251_0002
[00712] Compound 46A and 46B were prepared similarly to that of Ex.13. The solution was purified by prep-HPLC (eluting with CH3CN in H2O (0.1% TFA) from 5% to 95%) to give faster eluting P1 (46A).1H NMR (400 MHz, CD3OD) δ 7.372-7.333 (m, 1 H), 7.281-7.162 (m, 2 H), 5.597 (d, J=50.8 Hz, 1 H), 4.767-4.541 (m, 4 H), 4.146-3.764 (m, 5 H), 3.535-3.405 (m, 1 H), 3.289-2.944 (m, 6 H), 2.770–2.557 (m, 2 H), 2.487-2.203 (m, 6H), 1.971-1.676 (m, 4 H), 1.332 (s, 3 H) and slower eluting P2 (46B).1H NMR (400 MHz, CD3OD) δ 7.357-7.322 (m, 1 H), 7.244-7.069 (m, 2 H), 5.574 (d, J=52 Hz, 1 H), 4.635-4.440 (m, 4 H), 4.151-3.969 (m, 2 H), 3.909-3.809 (m, 3 H), 3.496-3.382 (m, 1 H), 3.184-2.912 (m, 6 H), 2.738–2.534 (m, 2 H), 2.455- 2.135 (m, 6H), 2.031-1.592 (m, 4 H), 1.293(s, 3 H). [00713] Compound 47.3-chloro-5-[(7S)-4'-chloro-2-[[1-(morpholinomethyl)cyclopropyl] methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000252_0001
[00714] Compound 47 was prepared from 27B-a similarly to that of Ex.11 as a formic acid salt. LCMS calcld for C33H38Cl2FN7O3 (M+H)+ m/z = 670.4, found: 670.4.1H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 7.32 (d, J = 7.1 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.12 (d, J = 6.9 Hz, 1H), 4.78 (d, J = 10.8 Hz, 3H), 4.59 (d, J = 14.2 Hz, 1H), 4.43 (d, J = 4.3 Hz, 2H), 4.26 – 4.14 (m, 2H), 3.85 (d, J = 5.7 Hz, 2H), 3.67 (t, J = 4.4 Hz, 4H), 3.10 (t, J = 8.1 Hz, 7H), 3.02 – 2.85 (m, 3H), 2.56 (d, J = 36.2 Hz, 6H), 2.39 (ddd, J = 12.1, 7.8, 4.1 Hz, 1H), 2.23 (dd, J = 12.1, 6.8 Hz, 3H), 0.66 (s, 2H), 0.50 (s, 2H). [00715] Compound 48.5-[4'-(difluoromethoxy)-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000252_0002
[00716] Compound 48 was prepared similarly to that of Ex.9 as a formic acid salt. LCMS calcld for C34H40F3N7O4 (M+H)+ m/z = 668.4, found: 668.4.1H NMR (400 MHz, DMSO) δ 7.53 – 7.30 (m, 2H), 7.28 – 7.14 (m, 1H), 7.11 – 6.90 (m, 1H), 6.53 (s, 1H), 5.56 (d, J = 52.8 Hz, 1H), 4.73 (d, J = 14.5 Hz, 3H), 4.45 (dd, J = 30.2, 13.4 Hz, 5H), 4.11 – 3.72 (m, 6H), 3.25 (s, 6H), 3.11 – 2.54 (m, 8H), 2.26 – 1.84 (m, 6H).19F NMR (377 MHz, CDCl3) δ -80.44 (dd, J = 129.9, 23.5 Hz), -171.65 (d, J = 32.3 Hz). [00717] Example 16. Exemplary synthesis of [3-chloro-5-[(7S)-4'-chloro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine- 7,1'-indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl- methanone (49)
Figure imgf000253_0001
[00718] Step 1. A solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (55.23mg, 0.35mmol) in DMSO (1mL) was added sodium hydride (20.82mg, 0.52mmol) at 25 oC for 0.5 h. After 0.5h, a solution of [ethyl 3-chloro-5-[(7S)-4'-chloro-2- methylsulfinyl-spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate (49a, prepared similarly to that of 27d of Ex.11) (100.mg, 0.17mmol) in DMSO (1mL) was added to above solution at 25 °C for 0.5 h. The mixture was poured into the mixture of NH4Cl (10 mL) and iced water (10 mL), extracted with DCM/MeOH(10:1)(10*3 mL), dried over Na2SO4, concentrated. Water was added (10 mL) to the residue and the resulting precipitate was filtered, and dried under vaccum to afford 3- chloro-5-[(7S)-4'-chloro-2-[[(2R,8R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methyl]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (49b) (50 mg , 0.0717 mmol, 41.34 % yield) was obtained as a white solid [00719] Step 2. To a solution of 3-chloro-5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (49b) (40.mg, 0.06mmol) and DIEA (24.1mg, 0.19mmol) in DCM (3mL) was added HATU (30.79uL, 0.12mmol) at 0 °C. The mixture was stirred at 25 °C for 10 min. Then, Piperazine (53.54mg, 0.62mmol) was added at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was concentrated to afford a crude product. The crude product was purified by Prep-HPLC. [3-chloro-5-[(7S)-4'-chloro-2-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3- d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin- 1-yl-methanone (49) (11 mg , 0.0135 mmol, 21.68 % yield) was obtained as white solid. LCMS calcld for C35H42Cl2FN8O3 (M+H)+ m/z = 711.3, found: 711.3.1H NMR (400 MHz, CD3OD) δ 7.32 (d, J = 7.8 Hz, 1H), 7.54 - 7.52 (m, 1H), 7.11 (d, J = 7.8 Hz, 1H), 5.36 - 5.19 (m, 1H), 4.82 – 4.74 (m, 2H), 4.58 (d, J = 14.2 Hz, 1H), 4.44 - 4.41 (m, 2H), 4.10 – 4.01 (m, 2H), 3.85 (brs, 2H), 3.71 (brs, 2H), 3.56 (brs, 2H), 3.20 – 3.05 (m, 3H), 3.00 - 2.92 (m, 4H), 2.90 - 2.84 (m, 3H), 2.80 (brs, 2H), 2.42 – 2.31 (m, 1H), 2.25 - 2.17 (m, 5H), 2.12 – 1.86 (m, 5H).19F NMR (377 MHz, CD3OD) δ -173.42 (s). [00720] Compound 50. [3-chloro-5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-(4-methylpiperazin-1-yl)methanone
Figure imgf000254_0001
[00721] Compound 50 was prepared similarly to that of Ex.16. LCMS calcld for C36H44Cl2FN8O3 (M+H)+ m/z = 725.3, found: 725.3.1H NMR (400 MHz, CD3OD) δ 7.32 (d, J = 8.0 Hz, 1H), 7.20 (m, 1H), 7.11 (d, J = 8.0 Hz, 1H), 5.35 - 5.22 (m, 1H), 4.88 - 4.74 (m, 3H), 4.58 (d, J = 14.3 Hz, 1H), 4.43 – 4.41 (m, 2H), 4.75 (d, J = 4.0 Hz, 1H), 3.85 (brs, 2H), 3.75 (brs, 2H), 3.63 (brs, 2H), 3.20 – 3.04 (m, 3H), 3.02 – 2.88 (m, 4H), 2.51 (brs, 2H), 2.44 (brs, 2H), 2.40 – 2.35 (m, 1H), 2.32 (s, 3H), 2.29 - 2.17 (m, 5H), 2.12 - 1.82 (m, 6H).19F NMR (377 MHz, CD3OD) δ -173.41 (s). [00722] Compound 51A and 51B. (5R)-9-[(7*)-5'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7'-hydroxy-spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'- tetralin]-4-yl]-1,3,9-triazaspiro[4.5]decane-2,4-dione
Figure imgf000254_0002
[00723] Compound 51A and 51B were prepared similarly to that of Ex.9. The mixture was purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase: H2O (0.1% NH4HCO3) / MeCN at flow rate: 35 mL/min to afford to give faster eluting P1 (51A):1H NMR (400 MHz, CD3OD) δ 6.78 (d, J = 2.4 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 5.29 (d, J = 54.4 Hz, 1H), 4.78 – 4.82 (m, 2H), 4.12 (s, 2H), 4.07 (d, J = 13.2 Hz, 1H), 3.68 (d, J = 13.2 Hz, 1H), 3.37 (d, J = 13.2 Hz, 1H), 3.15 – 3.28 (m, 4H), 3.01 (s, 1H), 2.95 (d, J = 11.2 Hz, 1H), 2.62 – 2.83 (m, 3H), 2.03 – 2.36 (m, 7H), 1.78 – 1.98 (m, 7H); and slower eluting P2 (51B):1H NMR (400 MHz, CD3OD) δ 6.78 (d, J = 2.4 Hz, 1H), 6.76 (d, J = 2.8 Hz, 1H), 5.32 (d, J = 53.6 Hz, 1H), 4.79 – 4.81 (m, 2H), 4.13 – 4.21 (m, 2H), 4.03 (d, J = 13.2 Hz, 1H), 3.76 (d, J = 13.6 Hz, 1H), 3.35 (d, J = 6.0 Hz, 1H), 2.99 – 3.14 (m, 4H), 2.96 (d, J = 8.4 Hz, 1H), 2.62 – 2.83 (m, 4H), 1.83 – 2.21 (m, 14H). Benzyl (R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-carboxylate (P2) was separated on a CHRALCEL OZ-3 column from a racemic mixture. The faster eluting P1 was determined as an S enantiomer by a single crystal structure. Removal of Cbz from P2 under hydrogenation conditions afforded (R)-1,3,7-triazaspiro[4.5]decane-2,4-dione, which was used to prepare compounds 51A and 51B. [00724] Example 17. Exemplary synthesis of [3-chloro-5-[(7S)-4'-chloro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine- 7,1'-indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-(1-imino-1-oxo-1,4- thiazinan-4-yl)methanone (52)
Figure imgf000255_0001
[00725] Step 1. To a solution of 3-chloro-5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (49b) (50.mg, 0.08mmol) and DIEA (30.12mg, 0.23mmol) in DMF (3mL) was added HATU (59.09mg, 0.16mmol) at 0 °C. The mixture was stirred at 25 °C for 10 min. Then, thiomorpholine (16.03mg, 0.16mmol) was added at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (20 mL), lots of white solid emerged. The mixture was filtered, and the crude product was recrystallized from EtOAc/PE/MeOH (2 mL/2 mL/0.5 mL) to afford [3-chloro-5-[(7S)-4'-chloro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]-thiomorpholino-methanone (52a) (35mg, 0.031mmol, 40% yield). [00726] Step 2. The mixture of [3-chloro-5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-thiomorpholino-methanone (52a) (25.mg, 0.03mmol), Iodobenzene Diacetate (23.21mg, 0.07mmol) and Ammonium acetate (4.23mg, 0.05mmol) in Methanol (3mL) was stirred at 25 °C for 2 h. The mixture was quenched with H2O (10 mL) and Na2SO3 (2 mL) at 25 °C, extracted with DCM/MeOH(10/1) (5*3 mL), dried over Na2SO4 and concentrated. The crude product was purified by Prep-HPLC to afford [3-chloro-5- [(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]-(1-imino-1-oxo-1,4-thiazinan-4-yl)methanone (52) (3mg,0.0037mmol, 11% yield). LCMS calcld for C35H42Cl2FN8O4S (M+H)+ m/z = 759.2, found: 759.3.1H NMR (400 MHz, CD3OD) δ 7.32 (d, J = 8.0 Hz, 1H), 7.22 - 7.18 (m, 1H), 7.11 (d, J = 8.0 Hz, 1H), 5.37 - 5.18 (m, 2H), 4.81 - 4.75 (m, 2H), 4.58 (d, J = 14.3 Hz, 2H), 4.48 – 4.41 (m, 2H), 4.38 - 4.18 (m, 2H), 4.12 – 3.92 (m, 4H), 3.89 - 3.81 (m, 2H), 3.25 - 3.05 (m, 6H), 3.05 – 2.88 (m, 4H), 2.35 – 1.88 (m, 11H).19F NMR (376 MHz, CD3OD) δ -173.40 (s). [00727] Example 18.3-chloro-5-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N- dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (53)
Figure imgf000256_0001
[00728] Step 1. To a solution of Ethyl Acetate (10.89 mL, 111.2 mmol) in THF (80 mL) was added LDA (55.60 mL, 111.20 mmol) drop wise at -70 ℃ under N2. Then the mixture was stirred at -70 ℃ for 3 h, and triisopropoxytitanium (IV) chloride (118.61 mL, 118.61 mmol) was added drop wise at same temperature and stirred for 30 min, then (R,E)-N-(4-chloro-2,3-dihydro- 1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide (28A-a) (10.00 g, 37.07 mmol) was added drop wise. The resulting mixture was stirred further 3h at -70 ℃. Then quenched with NH4Cl solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 50% EtOAc/PE) to afford the product ethyl 2-[(1S)-1-[[(R)-tert-butylsulfinyl]amino]-4- chloro-indan-1-yl]acetate (53a) (7.90 g, 22.10 mmol, 59.55 % yield) as yellow solid. LCMS calculated for C17H24ClNO3SNa (M+Na)+ m/z =380.11, 382.10; found: 380.3, 382.3. [00729] Step 2. To the mixture of ethyl 2-[(1S)-1-[[(R)-tert-butylsulfinyl]amino]-4-chloro- indan-1-yl]acetate (53a) (7.90 g, 22.07 mmol) in Ethanol (70 mL) was added the solution of HCl/dioxane (22.07 mL, 88.29 mmol) and the mixture was stirred at room temperature for 1 h. The solvent was removed by concentration to afford crude ethyl 2-[(1S)-1-amino-4-chloro- indan-1-yl]acetate hydrochloride (53b) (6.40 g, 22.1 mmol, 99.92 % yield), which was used directly in the next step. LCMS calculated for C13H18ClNO2 (M+H)+ m/z =290.07, 292.07; found: 151.1, 152.1 [00730] Step 3. The mixture of ethyl 2-[(1S)-1-amino-4-chloro-indan-1- yl]acetate;hydrochloride (53b) (6.40 g, 22.05 mmol), ethyl prop-2-enoate (15.46 g, 154.38 mmol), Et3N (9.23 mL, 66.16 mmol) and CuO (0.35 g, 4.41 mmol) in Ethanol (50 mL) was heated to 85 ℃ in a seal tube. The crude reaction mixture was filtered, and filtrate was concentrated in vacuo to give the crude product, which was purified by flash column chromatography (silica gel, eluting with 0% to 50% PE/EtOAc) to afford ethyl 3-[[(1S)-4- chloro-1-(2-ethoxy-2-oxo-ethyl)indan-1-yl]amino]propanoate (53c) (7.30 g , 20.6 mmol, 93.54 % yield) as a colorless oil. LCMS calculated for C18H25ClNO4 (M+H)+ m/z =354.15, 356.14; found: 354.3, 356.3. [00731] Step 4. The mixture of ethyl 3-[[(1S)-4-chloro-1-(2-ethoxy-2-oxo-ethyl)indan-1- yl]amino]propanoate (53c) (2.00 g, 5.65 mmol), Paraformaldehyde (2.04 g, 67.83 mmol) and NaBH₃CN (1.07 g, 16.96 mmol) in Ethanol (20 mL) was stirred at 25 ℃ for 16 h. The reaction mixture was quenched with water, and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 20% EtOAc/PE) to afford ethyl 3-[[(1S)-4-chloro-1-(2-ethoxy-2-oxo- ethyl)indan-1-yl]-methyl-amino]propanoate (53d) (1.90 g , 5.16 mmol, 91.38 % yield) as a yellow oil. LCMS calculated for C19H27ClNO4 (M+H)+ m/z =368.16, 370.16; found: 368.3, 370.3. [00732] Step 5. To a solution of ethyl 3-[[(1S)-4-chloro-1-(2-ethoxy-2-oxo-ethyl)indan-1-yl]- methyl-amino]propanoate (53d) (1.10 g, 2.99 mmol) in THF (11 mL) was added [bis(trimethylsilyl)amino]potassium (8.97 mL, 8.97 mmol) dropwise at -70 ℃ under N2. The mixture was stirred at same temperature for 2 h. The reaction mixture was quenched with NH4Cl at -70 ℃, and then extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, concentrated, and purified by flash column chromatography (silica gel, eluting with 0% to 20% EtOAc/PE) to afford ethyl (1S)-4-chloro-1'-methyl-4'-oxo-spiro[indane- 1,6'-piperidine]-3'-carboxylate (53e) (860 mg, 2.67 mmol, 89.37 % yield) as a yellow oil. LCMS calculated for C17H21ClNO3 (M+H)+ m/z =322.12, 324.12; found: 322.3, 324.3. [00733] Step 6. To a solution of ethyl (1S)-4-chloro-1'-methyl-4'-oxo-spiro[indane-1,6'- piperidine]-3'-carboxylate (53e) (860.00 mg, 2.67 mmol) in Ethanol (10 mL) was added Thiourea (406.86 mg, 5.34 mmol) and C2H5ONa (545.58 mg, 8.02 mmol). Then the mixture was stirred at 80 ℃ under N2 for 12 h. The reaction mixture was concentrated, then adjust pH to 6 with hydrochloric acid (1N), precipitate the solid, filter and dry the filter cake to afford (7S)-4'- chloro-6-methyl-2-sulfanyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4-ol (53f) (890.00 mg, 2.67 mmol, 99.76 % yield) as brown solid. LCMS calculated for C16H17ClN3OS (M+H)+ m/z =334.08, 336.07; found: 334.2, 334.2. [00734] Step 7. To a solution of (7S)-4'-chloro-6-methyl-2-sulfanyl-spiro[5,8- dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4-ol (53f) (890.0 mg, 2.67 mmol) in Water (10 mL) was added Chloroacetic Acid (1.26 g, 13.33 mmol) under N2. Then the mixture was stirred at 100 ℃ for 16 h. Upon completion, the reaction was filtered, and the pH of the filtrate was adjusted to 8 with NaHCO3 saturated aqueous. The solid was collected by filtration and dried to afford (7S)-4'-chloro-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-2,4-diol (53g) (614 mg , 1.93 mmol, 72.48% yield) as a brown solid. LCMS calculated for C16H17ClN3O2 (M+H)+ m/z =318.10, 320.10; found: 318.2, 320.3. [00735] Step 8. The mixture of (7S)-4'-chloro-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-indane]-2,4-diol (53g) (590.0 mg, 1.86 mmol) in Phosphorus Oxychloride (4 mL, 42.91 mmol) was stirred at 100 ℃ for 5 h. LCMS showed SM was consumed, then concentrated, diluted with DCM and purified by flash column chromatography (silica gel, eluting with 0% to 100% EtOAc in PE). Then concentrated and diluted with EtOAc, washed with NaHCO3 aqueous and brine, dried over Na2SO4 and concentrated to afford (7S)-2,4,4'- trichloro-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-indane] (53h) ( 432.0 mg , 1.22 mmol, 65.60% yield) as a yellow solid. LCMS calculated for C16H15Cl3N3 (M+H)+ m/z =354.04, 356.03; found: 354.1, 356.1. [00736] Step 9. The mixture of (7S)-2,4,4'-trichloro-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-indane] (53h) (150.0 mg, 0.42 mmol), 3-chloro-N,N-dimethyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide;hydrochloride (118.07 mg, 0.42 mmol) and DIEA (109 mg, 0.85 mmol) in DMF (2 mL) was stirred at room temperature for 30 h. The reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 3% to 7% MeOH/DCM) to afford 3-chloro-5-[(7S)-2,4'-dichloro-6-methyl-spiro[5,8- dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (53i) (120.0 mg, 0.2139 mmol, 50.58 % yield) as a white solid. LCMS calculated for C26H29Cl3N7O (M+H)+ m/z =560.15, 562.15; found: 560.3, 562.3. [00737] Step 10. The mixture of 3-chloro-5-[(7S)-2,4'-dichloro-6-methyl-spiro[5,8- dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (53i) (20.0 mg, 0.036 mmol), [(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (7.38 mg, 0.046 mmol), Cs2CO3 (29.06 mg, 0.089 mmol), Pd2dba3 (3.27 mg, 0.004 mmol) and Ruphos (3.33 mg, 0.007 mmol) in Toluene (1 mL) was stirred at 110 ℃ for 10 h under N2. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The mixture was purified by flash column chromatography (silica gel, eluting with 0% to 12% MeOH / DCM) followed by prep-HPLC(0.1% NH4HCO3) to afford 3-chloro-5-[(7S)-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine- 2-carboxamide (53) (9.78 mg, 0.015 mmol, 42.25% yield) as a white solid. LCMS calculated for C34H43ClFN8O2 (M+H)+ m/z =649.32; found: 649.3.1H NMR (400 MHz, CD3OD) δ 7.13 – 7.34 (m, 4H), 5.26 (d, J = 54.4 Hz, 1H), 4.75 – 4.83 (m, 2H), 4.36 – 4.54 (m, 2H), 3.97 – 4.09 (m, 3H), 3.68 – 3.93 (m, 3H), 3.11 – 3.28 (m, 3H), 3.10 (s, 3H), 3.08 (s, 3H), 2.80 – 3.05 (m, 5H), 2.21 – 2.47 (m, 3H), 2.19 (s, 3H), 1.80 – 2.18 (m, 7H). [00738] Compound 54.3-chloro-N,N-dimethyl-5-[rac-(7S)-4'-chloro-2-[(6-methylene- 2,3,5,7-tetrahydro-1H-pyrrolizin-8-yl)methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'- indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000259_0001
[00739] Compound 54 was prepared from 27B-a similarly to that of Ex.11 as a formic acid salt. LCMS calcld for C34H40Cl2N7O3 (M+H)+ m/z = 664.3, found: 664.5/666.5.1H NMR (400 MHz, CD3OD) δ 7.32 (d, J = 7.9 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 7.4 Hz, 1H), 5.34 – 5.20 (m, 2H), 4.83 – 4.71 (m, 3H), 4.59 (d, J = 14.4 Hz, 1H), 4.48 – 4.32 (m, 4H), 4.28 (d, J = 14.5 Hz, 1H), 3.94 – 3.75 (m, 3H), 3.74 – 3.64 (m, 1H), 3.23 – 3.04 (m, 8H), 3.04 – 2.89 (m, 4H), 2.73 (d, J = 15.9 Hz, 1H), 2.45 – 2.28 (m, 2H), 2.28 – 2.00 (m, 6H). [00740] Example 19. Exemplary synthesis of 3-chloro-5-((S)-4-chloro-2'-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6'-methyl-2,3,5',8'-tetrahydro-6'H- spiro[indene-1,7'-pyrido[4,3-d]pyrimidin]-4'-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (55)
Figure imgf000260_0001
[00741] To a solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (76.63 mg, 0.48 mmol) in THF (1 mL) was added NaH (16.05 mg, 0.4 mmol) at 0℃ under N2. The mixture was stirred at rt for 1 h, and then 3-chloro-5-[(7S)-2,4'-dichloro-6-methyl-spiro[5,8- dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (53i) (90.0 mg, 0.16 mmol) was added. The resulting mixture was stirred at 70 ℃ for 16 h. The reaction mixture was quenched with 1M HCl in MeOH, concentrated, purified by flash column chromatography (silica gel, eluting with 0% to 15% MeOH/DCM), and then purified by prep-HPLC (0.1% NH4HCO3) to afford 3- chloro-5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6- methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (55) (44.52 mg, 0.0635 mmol, 39.55% yield) as a white solid. LCMS calculated for C34H42Cl2FN8O2 (M+H)+ m/z = 683.28, 685.28; found: 683.4, 685.4.1H NMR (400 MHz, CD3OD) δ 7.23 – 7.34 (m, 2H), 7.17 (dd, J = 7.2, 1.6 Hz, 1H), 5.27 (d, J = 54.0 Hz, 1H), 4.75 – 4.83 (m, 2H), 4.36 – 4.53 (m, 2H), 3.95 – 4.11 (m, 3H), 3.67 – 3.94 (m, 3H), 3.14 – 3.27 (m, 3H), 3.10 (s, 3H), 3.08 (s, 3H), 2.91 – 3.06 (m, 3H), 2.83 – 2.91 (m, 2H), 2.23 – 2.51 (m, 3H), 2.20 (s, 4H), 1.81 – 2.19 (m, 7H). [00742] Compound 56. [3-chloro-5-[(7R)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone (56)
Figure imgf000260_0002
[00743] Compound 56 was prepared similarly to that of Ex.16. LCMS calcld for C35H40Cl2FN7O5S (M+H)+ m/z = 760.2, found: 760.5. [00744] Example 20. Exemplary synthesis of 1-[3-chloro-5-[(7S)-4'-chloro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine- 7,1'-indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-N,N-dimethyl-
Figure imgf000261_0001
[00745] Step 1. To a solution of (7S)-4,4'-dichloro-2-methylsulfanyl-spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,1'-indane] (27B-a P2) (300.mg, 0.85mmol) in NMP (8mL) were added ethyl 3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (517.36mg, 2.12mmol) and DIPEA (329.26mg, 2.55mmol) at 25°C. The mixture was stirred at 100 °C for 16 h. The mixture was diluted with EtOAC (60 mL), washed with water (30*3 mL) and brine (30 ml), dried over Na2SO4, concentrated. The crude product was purified by flash chromatography (eluted with EtOAc in PE from 0% to 50%) to afford ethyl 3-chloro-5-[rac- (7S)-4'-chloro-2-methylsulfanyl-spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate (57a) (300 mg, 0.535 mmol, 63.03%)yield as a pale white solid. LCMS calcld for C26H27Cl2N5O3S (M+H)+ m/z = 560.1, found: 560.2. [00746] Step 2. To a solution of ethyl 3-chloro-5-[(7S)-4'-chloro-2-methylsulfanyl-spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxylate (57a) (65.mg, 0.12mmol) in DCM (1mL) was added diisobutylaluminium hydride (0.23mL, 0.23mmol) at -78 °C. The mixture was stirred at -78 °C for 1 h. IPA (1 mL) and water (1 mL) were added at -78 °C, and the reaction mixture was allow back to rt and stirred for 1 h. The mixture was diluted with DCM (20 mL) and filtered. The solution was washed with brine (20 mL), dried over Na2SO4, concentrated to provide the crude product 3-chloro-5-[(7S)-4'-chloro-2-methylsulfanyl-spiro[5,8-dihydropyrano[4,3-d]pyrimidine- 7,1'-indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbaldehyde (57b) (53mg,0.10mmol, 88.5% yield), which was used directly in the next step.. LCMS calcld for C24H23Cl2N5O2S (M+H)+ m/z =516.1 found: 516.2. [00747] Step 3. To a solution of 3-chloro-5-[(7S)-4'-chloro-2-methylsulfanyl-spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carbaldehyde (57b) (60.mg, 0.12mmol) in DCM (2mL) was added Dimethylamine (0.35mL, 0.35mmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. Then Sodium triacetoxyborohydride (73.91mg, 0.35mmol) and AcOH (0.7mg, 0.01mmol) was added the reaction. The mixture was stirred at 25 °C for 1 h. The mixture was quenched with H2O (20 mL) at 25 °C, extracted with DCM (20 mL x 3), dried over Na2SO4, concentrated. The crude product was purified by Prep-HPLC (eluted with CH3CN in H2O (0.1 % NH4HCO3) from 5.0% to 95%) to give 1-[3-chloro-5-[(7S)-4'-chloro-2-methylsulfanyl-spiro[5,8-dihydropyrano[4,3- d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-N,N- dimethyl-methanamine (57c) (34mg,0.0623mmol, 53.6% yield) as a white solid. LCMS calcld for C26H30Cl2N6OS (M+H)+ m/z = 545.2 found: 545.1. [00748] Step 4. To a solution of 1-[3-chloro-5-[(7S)-4'-chloro-2-methylsulfanyl-spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]-N,N-dimethyl-methanamine (57c) (40.mg, 0.07mmol) in THF (2mL) was added a solution of oxone (45.08mg, 0.15mmol) in Water (1mL) at 0 °C . Then the mixture was stirred at 25 °C for 3 h. The mixture was added water (30 mL) and extracted with EtOAC (40 mL x 3), washed with a solution of Na2SO3 (20 mL), brine (50 ml), dried over Na2SO4, concentrated in vacuum to give the crude product. The aqueous layer was adjusted to pH = 9 with the NaHCO3 solution. The mixture was extracted with EtOAC (40 mL x 3), dried over Na2SO4, concentrated in vacuum to give the crude product 1-[3-chloro-5-[(7S)-4'-chloro-2- methylsulfinyl-spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-N,N-dimethyl-methanamine (57d) (37 mg, 0.0659 mmol, 89.86 %yield) as a white solid. LCMS calcld for C26H30Cl2N6O2S (M+H)+ m/z = 561.2, found: 561.1. [00749] Step 5. To a solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (26.22mg, 0.16mmol) in DMF (1mL) was added NaH (5.27mg, 0.13mmol) at 25 °C. The mixture was stirred at 25 °C for 15 min. A solution of 1-[3-chloro-5-[(7S)-4'-chloro-2- methylsulfinyl-spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-N,N-dimethyl-methanamine (57d) (37.mg, 0.07mmol) in DMF (0.5mL) was added and the mixture was stirred at 25 °C for 1 h. Acetic acid (0.01mL, 0.13mmol) was added the reaction mixture. The crude product was purified by Prep- HPLC (FA) to afford 1-[3-chloro-5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-N,N-dimethyl-methanamine;formic acid (57) (24.13mg,0.034mmol, 51.60% yield) as a white solid. LCMS calcld for C33H40Cl2FN7O2 (M+H)+ m/z = 656.26, found: 656.3.1H NMR (400 MHz, CD3OD) δ 8.46 (s, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 7.4 Hz, 1H), 5.46 (d, J = 52.5 Hz, 1H), 4.79 (d, J = 12.4 Hz, 4H), 4.59 (d, J = 14.4 Hz, 1H), 4.45 (d, J = 5.2 Hz, 2H), 4.34 (s, 2H), 3.93 (s, 2H), 3.87 (s, 2H), 3.79 – 3.48 (m, 3H), 3.28 – 3.20 (m, 1H), 3.09 (dt, J = 21.4, 6.8 Hz, 1H), 3.03 – 2.86 (m, 3H), 2.63 (s, 6H), 2.58 – 2.32 (m, 3H), 2.29 – 2.13 (m, 6H), 2.04 (s, 1H). [00750] Compound 58. (5R)-9-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- indane]-4-yl]-1,3,9-triazaspiro[4.5]decane-2,4-dione
Figure imgf000263_0001
[00751] Compound 58 was prepared similarly to that of Ex.19. LCMS calculated for C31H38ClFN7O3 (M+H)+ m/z = 610.27, 611.27; found: 610.3, 611.3.1H NMR (400 MHz, CD3OD): δ 7.23 – 7.32 (m, 2H), 7.17 (dd, J = 6.9, 1.5 Hz, 1H), 5.26 (dd, J = 55.4, 3.3 Hz, 1H), 4.10 (q, J = 10.4 Hz, 2H), 3.95 (q, J = 13.5 Hz, 2H), 3.70 (q, J = 14.8 Hz, 2H), 3.39 (d, J = 13.2 Hz, 1H), 3.13 – 3.26 (m, 3H), 2.93 –3.12 (m, 4H), 2.89 (s, 2H), 2.40 – 2.51 (m, 1H), 2.21 – 2.32 (m, 1H), 2.19 (s, 3H), 2.06 – 2.18 (m, 3H), 1.81 –2.02 (m, 7H).19F NMR (376 MHz, CD3OD): δ -173.76 (s). Intermediate 1. Synthesis of 3-chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a]
Figure imgf000263_0002
Figure imgf000263_0003
[00752] Step 1. Synthesis of 2-nitro-N-prop-2-ynyl-benzenesulfonamide (Int-1a). A solution of prop-2-yn-1-amine (1.87 mL, 29.15 mmol) and N,N-Diisopropylethylamine (10.15mL, 58.3 mmol) in DCM (100 mL) was cooled to 0 °C.2-nitrobenzenesulfonyl chloride (6460.mg, 29.15 mmol) was added portion wise. Upon complete addition, the solution was allowed to warm to room temperature and was further stirred for 1 hr. The mixture was washed with water and brine, dried over Na2SO4, concentrated. The crude product was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 20% to 50%) to afford 2-nitro-N-prop-2-ynyl- benzenesulfonamide (Int-1a, 5984 mg, 24.9 mmol, 85.45 % yield) as a yellow solid. LCMS calculated for C9H9N2O4S (M+H)+ m/z = 241.0, found: 241.0. [00753] Step 2. Synthesis of N-(3-chloropropyl)-2-nitro-N-prop-2-ynyl-benzenesulfonamide (Int-1b). To a mixture of 2-nitro-N-prop-2-ynyl-benzenesulfonamide (Int-1a, 20.g, 83.25mmol) and K2CO3 (33.37g, 241.43mmol) in Acetone (200mL) was added neat 1-Bromo-3- Chloropropane (41.16mL, 416.25mmol) dropwise. Upon complete addition, the reaction mixture was stirred at 25 oC overnight. The mixture was diluted with EtOAC (300 mL), washed with water (100 mL) and brine (20 ml), dried over Na2SO4, concentrated. The mixture was concentrated, then washed with water and brine, dried over Na2SO4, concentrated. The crude product form 4 batches on the same scale were combined and purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 10% to 90%) to give N-(3- chloropropyl)-2-nitro-N-prop-2-ynyl-benzenesulfonamide (Int-1b, 87.00 g, 275 mmol, 82.48 % yield) as a yellow solid. LCMS calcld for C12H14ClN2O4S (M+H)+ m/z = 317.0, found: 317.0. [00754] Step 3. Synthesis of ethyl 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxylate (Int-1c). To solution of N-(3-chloropropyl)-2-nitro-N-prop-2- ynyl-benzenesulfonamide (Int-1b, 10g, 31.57mmol) and ethyl 2-diazoacetate (5403.14 mg, 47.35 mmol) in Chlorobenzene (80mL) was added N,N-Diisopropylethylamine (5.5 mL, 31.57 mmol) at 140 °C for 1.5 hours. Upon complete addition, cesium carbonate (12.31 g, 37.88 mmol) was added and again heated to 140 °C for 30 minutes. The solvent was concentrated, and the mixture was extracted with EtOAC, washed with brine, dried over Na2SO4, concentrated. The crude product was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 20% to 90%), then triturated in EtOAc to afford ethyl 5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate (Int-1c, 5.80 g, 14.7 mmol, 46.58 % yield) as a yellow solid. LCMS calcld for C16H19N4O6S (M+H)+ m/z = 395.1, found: 395.0. [00755] Step 4. Synthesis of ethyl 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxylate (Int-1d). To a solution of ethyl 5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate (Int-1c, 12.6 g, 31.95 mmol) in THF (100 mL) and Methanol (25 mL) a was added 1M LiOH in water (128 mL, 127.79 mmol) at 25 °C. The mixture was stirred at 55 °C for 2 h. The mixture was acidified with HCl (1mol/L in H2O) to pH= 6 and the crude product was triturated in water and filtered.5-(2-nitrophenyl)sulfonyl- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (Int-1d, 11.5 g , 31.1 mmol, 97.28 % yield) was obtained as a yellow solid. LCMS calcld for C14H14N4O6S (M+H)+ m/z = 367.1, found: 367.0. [00756] Step 5. Synthesis of N,N-dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Int-1e). To a solution of 5-(2- nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (Int-1d, 9.60 g, 26.2 mmol), DIEA (18.26 mL, 104.82 mmol) and HATU (14.946 g, 39.31 mmol) in DMF (90 mL) was added 2M N-methylmethanamine in THF (20 mL) at 30 °C. The mixture was stirred at 30 °C for 2h. The mixture was diluted with DCM (300x2 mL), washed with water (400 mL) and brine (400x2 mL), dried over Na2SO4 and concentrated to afford a crude product N,N- dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carboxamide (Int-1e, 10.1g, 24.4 mmol, 93.07 % yield) as a yellow oil. LCMS calcld for C16H20N4O3S (M+H)+ m/z =394.1, found: 394.2. [00757] Step 6. Synthesis of 3-chloro-N,N-dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Int-1f). To a solution of N,N-dimethyl- 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Int- 1e, 10.1 g, 25.67 mmol) in DMF (100 mL) was added N-Chlorosuccinimide (3.428 g, 25.67mmol) at 0 °C under argon. The mixture was stirred at 45 °C for 1h. The mixture was concentrated to afford a crude product. The crude product was triturated in water and filtered to afford 3-chloro-N,N-dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide (Int-1f, 10.2 g, 23.4 mmol, 91.00 % yield) as a crude yellow solid. LCMS calcld for C16H17ClN4O6S(M+H)+ m/z = 428.1, found: 428.0. [00758] Step 7. Synthesis of 3-chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide(Intermediate 1). To a solution of 3-chloro-N,N-dimethyl-5-(2- nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Int-1f, 10.2 g, 23.84 mmol) ,4-methoxybenzenethiol (8.8 mL, 71.52 mmol) and CS2CO3 (31.067 g, 95.36 mmol) in MeCN (100mL). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated and the crude product was purified by silica gel chromatography (eluted with MeOH in DCM from 3% to 10%) to afford 3-chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Int-1, 3.20 g, 13.2 mmol, 55.30 % yield) as a yellow solid. LCMS calcld for C10H15ClN4O (M+H)+ m/z = 243.1, found: 243.0. Intermediate 2. Synthesis of 2-methylsulfanyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine (Int-2)
Figure imgf000266_0001
[00759] Step 1. Synthesis of 1,1-dimethoxy-4,4-bis(methylsulfanyl)but-3-en-2-one (Int-2a). To a solution of sodium hydride (6.77 g, 169.31 mmol) in THF (100 mL) was added Carbon Disulfide (5.1 mL, 84.65 mmol) at 0 °C. The mixture was stirred at 25 °C for 10 min. Then, a solution of 1,1-dimethoxypropan-2-one (10 g, 84.65 mmol) in THF (30 mL) was added at 0 °C. The mixture was stirred at 25 °C for 2 h. Then, a solution of Methyl Iodide (6.35mL, 101.58mmol) in THF (30 mL) was added at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was poured into NaHCO3 (70 mL) and iced water (70 mL), extracted with EtOAC (100*3 mL), dried over Na2SO4, concentrated. The crude product was purified by flash chromatography (eluted with EtOAc in petroleum ether from 0% to 20%) to afford 1,1- dimethoxy-4,4-bis(methylsulfanyl)but-3-en-2-one (Int-2a, 6.00 g, 27.0 mmol, 31.88%yield) as a pale-yellow oil. [00760] Step 2. Synthesis of 5-(dimethoxymethyl)-3-methylsulfanyl-1H-pyrazole (Int-2b). To a solution of 1,1-dimethoxy-4,4-bis(methylsulfanyl)but-3-en-2-one (Int-2a, 11 g, 49.48 mmol) in Ethanol (210 mL) was added hydrazine;hydrate (10.11 g, 197.91 mmol) and the reaction mixture was stirred at 25 °C for 16 h. The mixture was poured into iced water (100 mL), extracted with EtOAC (100*3 mL), dried over Na2SO4, concentrated. The crude product was purified by flash chromatography (eluted with EtOAc in petroleum ether from 0% to 50%) to afford 5-(dimethoxymethyl)-3-methylsulfanyl-1H-pyrazole (Int-2b, 6.00 g, 31.9 mmol, 64.42 %yield) as a pale-yellow oil. [00761] Step 3. Synthesis of 3-methylsulfanyl-1H-pyrazole-5-carbaldehyde (Int-2c). To a solution of 5-(dimethoxymethyl)-3-methylsulfanyl-1H-pyrazole (Int-2b, 2.6 g, 13.81 mmol) in Acetone (30 mL) and Water (10 mL) was added p-Toluenesulfonic acid (1189.16 mg, 6.91 mmol) at 25 °C. The mixture was stirred at 50 °C for 2 h. The mixture was poured into the mixture of NH4Cl (30 mL) and iced water (30 mL). The mixture was filtered, and the filter cake was evaporated. The solid was dissolved with MeOH (20 mL) and filtered. The filter was dried under vacuum to give 3-methylsulfanyl-1H-pyrazole-5-carbaldehyde (Int-2c, 1.8 g,12.3 mmol, 89.19% yield) was obtained as a pale-yellow solid. LCMS calcld for C5H6N2OS (M+H)+ m/z = 143.0, found: 143.2. [00762] Step 4. Synthesis of 3-[(E)-(3-methylsulfanyl-1H-pyrazol-5- yl)methyleneamino]propan-1-ol (Int-2d). The solution of 3-methylsulfanyl-1H-pyrazole-5- carbaldehyde (Int-2c, 1.1 g, 7.74 mmol) and 3-aminopropan-1-ol (639.21 mg, 8.51 mmol) in Ethanol (10 mL) was stirred at 80 °C for 16 h. The mixture was concentrated to afford a crude product which was used directly in the next step.3-[(E)-(3-methylsulfanyl-1H-pyrazol-5- yl)methyleneamino]propan-1-ol (Int-2d, 1.7 g, 3.23 mmol, 41.80% yield) was obtained as crude yellow oil. LCMS calcld for C8H13N3OS (M-H)- m/z = 199.1, found: 199.1. [00763] Step 5. Synthesis of 3-[(3-methylsulfanyl-1H-pyrazol-5-yl)methylamino]propan-1-ol (Int-2e). To a solution of 3-[(E)-(3-methylsulfanyl-1H-pyrazol-5-yl)methyleneamino]propan-1- ol (Int-2d, 1.7 g, 8.53 mmol) in Methanol (30 mL) was added Sodium triacetoxyborohydride (3.62 g, 17.06 mmol) at 0 °C. The mixture was stirred at 25 °C for 6 h. The mixture was concentrated, and the crude product was purified by C18 flash chromatography (eluted with ACN in water from 0% to 7%) to give 3-[(3-methylsulfanyl-1H-pyrazol-5- yl)methylamino]propan-1-ol (Int-2e, 1.5 g, 7.45 mmol, 87.35% yield). LCMS calcld for C8H15N3OS (M+H)+ m/z = 202.2, found: 202.2. [00764] Step 6. Synthesis of tert-butyl N-(3-hydroxypropyl)-N-[(3-methylsulfanyl-1H- pyrazol-5-yl)methyl]carbamate (Int-2f). To a solution of 3-[(3-methylsulfanyl-1H-pyrazol-5- yl)methylamino]propan-1-ol (Int-2e, 100 mg, 0.5 mmol) and Et3N (0.14 mL, 0.99 mmol) in DCM (3 mL) was added Boc2O (0.14 mL, 0.6 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was diluted with DCM (10 mL) and filtered. The solution was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, concentrated. The crude product was purified by Prep-TLC (eluted with EtOAc 100%) to give tert-butyl N-(3-hydroxypropyl)-N-[(3- methylsulfanyl-1H-pyrazol-5-yl)methyl]carbamate (Int-2f, 50 mg, 0.15 mmol, 30% yield) as a colorless viscous semi-solid. LCMS calcld for C13H24N3O3S (M+H)+ m/z = 302.1, found: 302.1. [00765] Step 7. Synthesis of 3-[tert-butoxycarbonyl-[(3-methylsulfanyl-1H-pyrazol-5- yl)methyl]amino]propyl methanesulfonate (Int-2g). To a solution of tert-butyl N-(3- hydroxypropyl)-N-[(3-methylsulfanyl-1H-pyrazol-5-yl)methyl]carbamate (Int-2f, 50 mg, 0.17 mmol) and in DCM (2 mL) was added MsCl (28.5 mg, 0.25 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was quenched with H2O (20 mL), extracted with DCM (10*2 mL), dried over Na2SO4, concentrated. The crude product was purified by Prep-TLC (eluted with EtOAc in petroleum ether 50%) to give 3-[tert-butoxycarbonyl-[(3-methylsulfanyl- 1H-pyrazol-5-yl)methyl]amino]propyl methanesulfonate (Int-2g, 27 mg,0.069 mmol, 42% yield) as a colorless viscous semi-solid. LCMS calcld for C14H25N3O5S2 (M+Na)+ m/z = 402.1, found: 402.0. [00766] Step 8. Synthesis of tert-butyl 2-methylsulfanyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-5-carboxylate (Int-2h). To a solution of 3-[tert-butoxycarbonyl-[(3- methylsulfanyl-1H-pyrazol-5-yl)methyl]amino]propyl methanesulfonate (Int-2g, 200 mg, 0.53 mmol) in THF (20 mL) was added sodium hydride (63.24 mg, 1.58 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 3 h. The mixture was quenched with the mixture of NH4Cl (20 mL) and iced water (20 mL), extracted with EtOAC (20*3 mL), dried over Na2SO4, concentrated. The crude product was purified by flash chromatography (eluted with EtOAc in petroleum ether from 0% to 35%) to give tert-butyl 2-methylsulfanyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (Int-2h, 50 mg,0.176 mmol, 33.5% yield) as a yellow oil. LCMS calcld for C13H21N3O2 (M+H)+ m/z = 284.2, found: 284.2. [00767] Step 9. Synthesis of 2-methylsulfanyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine (Intermediate 2). To a solution of tert-butyl 2-methylsulfanyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (Int-2h, 40 mg, 0.14 mmol) in DCM (2 mL) was added TFA (0.5 mL, 6.53 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was transferred dropwise onto a saturated aqueous solution of NaHCO3 (20 mL), extracted with DCM (3x10mL), dried over Na2SO4, concentrated. the crude product was purified by Prep-TLC (eluted with MeOH in DCM of 10%) to give 2-methylsulfanyl-5,6,7,8-tetrahydro- 4H-pyrazolo[1,5-a][1,4]diazepine (Intermediate 2, 8 mg, 0.044 mmol, 31% yield) a yellow oil. LCMS calcld for C8H13N3S (M+H)+ m/z = 184.1, found: 184.2. [00768] Compound 59.1-[3-chloro-5-[(7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-N-methyl-methanamine
Figure imgf000268_0001
[00769] Compound 59 was prepared similarly to that of Ex.20. LCMS calcld for C33H40Cl2FN7O2 (M+H)+ m/z = 642.59, found: 642.3.1H NMR (DMSO-d6, 400Hz): δ 7.39 (d, J = 8.4 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 5.32-5.19 (m, 1H), 4.76-4.70 (m, 3H), 4.50-4.47 (m, 1H), 4.32-4.32 (m, 2H), 3.93 (d, J = 10.4 Hz, 1H), 3.84 (d, J = 10.4 Hz, 1H), 3.75-3.74 (m, 3H), 3.51 (s, 3H), 3.07-3.04 (m, 3H), 3.00-2.97 (m, 2H), 2.93-2.90 (m, 3H), 2.84-2.79 (m, 1H), 2.33-2.30 (m, 2H), 2.25 (s, 3H), 2.17-2.10 (m, 1H), 2.09-2.01 (m, 3H), 1.99- 1.98 (m, 1H), 1.93-1.91 (m, 1H). [00770] Compound 60. (5R)-9-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-1,3,9- triazaspiro[4.5]decane-2,4-dione
Figure imgf000269_0001
[00771] Compound 60 was prepared similarly to that of Ex.19. LCMS calculated for C31H39FN7O3 (M+H)+ m/z =576.31; found: 576.3.1H NMR (400 MHz, CD3OD) δ 7.17 – 7.30 (m, 4H), 5.32 (d, J = 53.6 Hz, 1H), 4.21, 4.13 (d, J = 10.8 Hz, 2H), 3.99 (d, J = 13.2 Hz, 1H), 3.91 (d, J = 12.8 Hz, 1H), 3.75, 3.66 (d, J = 14.8 Hz, 2H), 3.40 (d, J = 13.2 Hz, 1H), 3.24 – 3.36 (m, 3H), 2.93 – 3.11 (m, 6H), 2.22 – 2.47 (m, 3H), 2.19 (s, 3H), 1.83 – 2.17 (m, 9H). [00772] Compound 61.3-chloro-5-[(7S)-4',7'-difluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- indane]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000269_0002
[00773] Compound 61 was prepared similarly to that of Ex.18. LCMS calculated for C34H41ClF3N8O2 (M+H)+ m/z =685.3; found:685.3.1H NMR (400 MHz, CD3OD) δ 7.04 (td, J = 8.8, 3.6 Hz, 1H), 6.97 (td, J = 9.2, 4.0 Hz, 1H), 5.27 (d, J = 54.0 Hz, 1H), 4.80 (d, J = 6.8 Hz, 2H), 4.35 – 4.51 (m, 2H), 4.01, 4.07 (d, J = 10.8 Hz, 2H), 3.99-4.10 (m, 1H), 3.83 – 3.92 (m, 1H), 3.65, 3.79 (d, J = 14.8 Hz, 2H), 3.14 – 3.25 (m, 3H), 3.05 – 3.12 (m, 1H), 3.10 (s, 3H), 3.08 (s, 3H), 2.92 – 3.02 (m, 2H), 2.87 (d, J = 18.0 Hz, 1H), 2.30 – 2.58 (m, 3H), 2.28 (s, 3H), 2.03 – 2.23 (m, 4H), 1.82 – 2.00 (m, 4H). [00774] Compound 62. (7S)-4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]-4-(2-methylsulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-5- yl)spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]
Figure imgf000270_0001
[00775] Compound 62 was prepared similarly to that of Ex.11 using intermediate 2. LCMS calcld for C31H36ClFN6O4S (M+H)+ m/z = 643.2, found: 643.3.1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 7.6 Hz, 1H), 7.26 - 7.23 (m, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.67 (brs, 1H), 5.31 (d, J = 53.2 Hz, 1H), 4.68 – 4.32 (m, 6H), 4.11 - 4.04 (m, 3H), 3.69 - 3.63 (m, 1H), 3.43 – 3.08 (m, 8H), 3.06 – 2.85 (m, 3H), 2.40 - 2.14 (m, 6H), 2.07 – 1.89 (m, 4H).19F NMR (377 MHz, CDCl3) δ -172.99 (s). [00776] Compound 63.3-chloro-5-[(7S)-7'-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- indane]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000270_0002
[00777] Compound 63 was prepared similarly to that of Ex.18. LCMS calculated for C34H42ClF2N8O2 (M+H)+ m/z = 667.31, 668.31; found: 667.2, 668.2.1H NMR (400 MHz, CD3OD) δ = 7.31 (td, J=7.9, 5.1, 1H), 7.09 (d, J=7.5, 1H), 6.93 (dd, J=10.1, 8.4, 1H), 5.26 (d, J=54.6, 1H), 4.75-4.81 (m, 2H), 4.35 – 4.52 (m, 2H), 3.96 – 4.09 (m, 3H), 3.83 – 3.92 (m, 1H), 3.73 (d, J= 14.6, 2H), 3.11 – 3.28 (m, 4H), 3.10 (s, 3H), 3.08 (s, 3H), 2.93 –3.07 (m, 3H), 2.85 (d, J=18.0, 1H), 2.48 (dt, J=13.2, 8.6, 1H), 2.29 – 2.43 (m, 1H), 2.26 (s, 3H), 2.02 – 2.23 (m, 4H), 1.79 – 2.00 (m, 4H).19F NMR (376 MHz, CD3OD) δ = -120.88 (s), -173.46 (s). Example 21. Exemplary synthesis of 3-chloro-5-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 64).
Figure imgf000271_0001
[00778] Step 1. Synthesis of (NE,R)-2-methyl-N-tetralin-1-ylidene-propane-2-sulfinamide (64a). A mixture of (R)-2-methylpropane-2-sulfinamide (24.87g, 205.21mmol) and tetraethoxytitanium (42.95mL, 205.21mmol) in Toluene (100mL) was stirred and heated to 90 °C. Then the tetralin-1-one (10.g, 68.4mmol) was added to mixture dropwise and stirred for 5h. The mixture was quenched with Potassium sodium tartrate tetrahydrate (aq, 600 mL), filtered and extract with ethyl acetate and purified by flash column chromatography (silica gel, eluting with 10% to 30% EtOAc/PE) to afford (NE,R)-2-methyl-N-tetralin-1-ylidene-propane-2-sulfinamide (64a, 13.60 g, 54.5 mmol, 79.73 %yield )as a brown oil. LCMS calculated for C14H20NOS (M+H)+ m/z = 250.1; found: 250.1. [00779] Step 2. Synthesis of ethyl 2-[(1S)-1-[[(R)-tert-butylsulfinyl]amino]tetralin-1-yl]acetate (64b). To a solution of Diisopropylamine (16.49mL, 117.34mmol) in THF (230mL) was added butyllithium (44.8 mL, 112 mmol) portion wise at 0 °C under N2. Then the mixture was stirred at 0 °C for 0.5h then cooled to -70 °C to which was added EtOAc (10.44 mL, 106.67 mmol). The solution was stirred for 1 h upon which was added triisopropoxytitanium(IV) chloride (213.34 mL, 213.34 mmol) at -70 °C and stirred for 30 min, then (NE,R)-2-methyl-N-tetralin-1-ylidene- propane-2-sulfinamide (64a, 13.3 g, 53.33 mmol) in THF (34 mL) was added drop wise at -70 °C. The resulting mixture was stirred at-70 °C for 2h. Then quenched with NH4Cl at -70 °C, extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 5% to 34% EtOAc/PE) to afford ethyl 2-[(1S)-1-[[(R)-tert-butylsulfinyl]amino]tetralin-1-yl]acetate (64b, 15.43 g, 45.7 mmol, 85.74 %yield) as a yellow oil. LCMS calculated for C18H28NO3S (M+H)+ m/z =338.18, found: 338.3. [00780] Step 3. Synthesis of ethyl 2-[(1S)-1-amino-7-fluoro-indan-1-yl]acetate (64c). The mixture of ethyl 2-[(1S)-1-[[(S)-tert-butylsulfinyl]amino]tetralin-1-yl]acetate (64b, 2.37 g, 7.02 mmol) and HCL/dioxane (7.02 mL, 28.09 mmol) in Ethanol (8 mL) was stirred at rt for 1 h. Aqueous ammonia was added to the reaction mixture until pH adjusted to 9, then the reaction mixture was extracted with EtOAc, The crude reaction mixture was purified by Prep-HPLC to afford crude ethyl 2-[(1S)-1-amino-7-fluoro-indan-1-yl]acetate (64c) as a brown oil. LCMS calculated for C14H19NO2 (M+H)+ m/z = 217.2; found: 217.1 [00781] Step 4. Synthesis of ethyl 3-[[(1S)-1-(2-ethoxy-2-oxo-ethyl)tetralin-1- yl]amino]propanoate (64d). A mixture of ethyl 2-[(1S)-1-aminotetralin-1-yl]acetate (64c, 1.55 g, 6.64 mmol), ethyl prop-2-enoate (4.66 g, 46.5 mmol), Et3N (2.78 mL, 19.93 mmol) and CuO (0.11 g, 1.33 mmol) was dissolved in Ethanol (20 mL). The vial was sealed, and this mixture was then stirred for 8h at 85 °C. The crude reaction mixture was filtered and purified by flash column chromatography (silica gel, eluting with 0% to 50% PE/EA) to afford ethyl 3-[[(1S)-1-(2-ethoxy- 2-oxo-ethyl)tetralin-1-yl]amino]propanoate (64d, 2000 mg, 6.00 mmol, 90.29 %yield) as a light- yellow oil. LCMS calculated for C19H28NO4 (M+H)+ m/z = 334.2; found: 334.2. [00782] Step 5. Synthesis of ethyl 3-[methyl-[(1S)-1-(2-ethoxy-2-oxo-ethyl)tetralin-1- yl]amino]propanoate (64e). To a solution of ethyl 3-[[(1S)-1-(2-ethoxy-2-oxo-ethyl)tetralin-1- yl]amino]propanoate (64d, 2 g, 6 mmol) in Ethanol (80 mL) was added Paraformaldehyde (1.08 g, 35.99 mmol) and CH3BNNa (1.13 g, 18 mmol) . Then the mixture was stirred at 25 °C for 16h, the reaction mixture was quenched with water, and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 20% EtOAc/PE) to afford ethyl 3-[methyl-[(1S)-1- (2-ethoxy-2-oxo-ethyl)tetralin-1-yl]amino]propanoate (64e, 1680 mg, 4.84 mmol, 80.61 %yield) as a colorless oil. LCMS calculated for C20H30NO4 (M+H)+ m/z = 348.2; found: 348.2. [00783] Step 6. Synthesis of ethyl (6S)-1-methyl-4-oxo-spiro[piperidine-6,1'-tetralin]-3- carboxylate (64f). To a solution of [bis(trimethylsilyl)amino]potassium (14.5mL) in THF (8mL) was added ethyl 3-[methyl-[(1S)-1-(2-ethoxy-2-oxo-ethyl)tetralin-1-yl]amino]propanoate (64e, 1.68 g, 4.84mmol) portion wise at -70 °C under N2. Then the mixture was stirred at -70 °C for 2h. The reaction mixture was quenched with NH4Cl at -70 °C, and then extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, concentrated, and purified by flash column chromatography (silica gel, eluting with 0% to 20% EtOAc/PE) to afford ethyl (6S)- 1-methyl-4-oxo-spiro[piperidine-6,1'-tetralin]-3-carboxylate (64f, 1300 mg, 4.31 mmol, 89.21 % yield) as a yellow oil. LCMS calculated for C18H23NO3 (M+H)+ m/z = 302.2; found: 302.3. [00784] Step 7. Synthesis of (7S)-6-methyl-2-sulfanyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-tetralin]-4-ol (64g). To a solution of ethyl (6S)-1-methyl-4-oxo- spiro[piperidine-6,1'-tetralin]-3-carboxylate (64f, 1300 mg, 4.31 mmol) in Ethanol (10 mL) was added Thiourea (656.69 mg, 8.63 mmol) and C2H5ONa (880.6 mg, 12.94 mmol). Then the mixture was stirred at 80 °C under N2 for 12h. The reaction mixture was concentrated, then pH was adjusted to 6 with hydrochloric acid (1N), the resulting precipitate was filtered to afford (7S)-6-methyl-2- sulfanyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-4-ol (64g, 1000 mg, 3.19 mmol, 73.97 % yield as yellow solid. LCMS calculated for C17H19N3OS (M+H)+ m/z =314.13; found: 314.0. [00785] Step 8. Synthesis of (7S)-6-methylspiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-2,4-diol (64h). To a solution of (7S)-6-methyl-2-sulfanyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-tetralin]-4-ol (64g, 1 g, 3.19 mmol) in Water (12 mL) was added Chloroacetic Acid (1.51 g, 15.95 mmol) under N2. Then the mixture was stirred at 100 °C for 16h. The reaction was filtered, and the pH of the filtrate was adjusted to 8 with NaHCO3. The solid was collected by filtration and dried to afford (7S)-6-methylspiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-2,4-diol (64h, 913 mg, 3.07 mmol, 96.23 %yield) as a white solid. LCMS calculated for C17H20N3O2 (M+H)+ m/z = 298.15; found: 298.1. [00786] Step 9. Synthesis of (7S)-2,4-dichloro-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-tetralin] (64i). The mixture of (7S)-6-methylspiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-tetralin]-2,4-diol (64h, 300 mg, 1.01 mmol) in POCl3 (3.21 mL, 35.02 mmol) was stirred at 100 °C for 4.5 h. The reaction was concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 100% EtOAc/PE) to afford (7S)-2,4-dichloro-6- methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin] (64i, 360 mg, 0.808 mmol, 80.07 %yield) as an orange solid. LCMS calculated for C17H18Cl2N3 (M+H)+ m/z =334.1, 336.1; found: 334.0/336.0 [00787] Step 10. Synthesis of -chloro-5-[(7S)-2-chloro-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-tetralin]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine- 2-carboxamide (64j). To a solution of (7S)-2,4-dichloro-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-tetralin] (64i, 3 g, 8.98 mmol) in DMSO (30 mL). 3-chloro-N,N-dimethyl- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Int-1, 2724 mg, 11.22 mmol) and DIEA (4.69 mL, 26.93 mmol) were added. The reaction was stirred at 20 °C over weekends. Then the mixture was filtered and purified by Prep-HPLC on a C18 column (5uM, 50 x 150 mm) with mobile phase: H2O (0.1% NH4HCO3) / MeCN at flow rate: 65mL/min to afford 3-chloro-5-[(7S)-2-chloro-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-4- yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (64j, 3525 mg, 6.52 mmol, 72.66 % yield) as a white solid. LCMS calculated for C27H31Cl2N7O (M+H)+ m/z =540.20, 542.20; found: 540.1, 542.1. [00788] Step 11. Synthesis of 3-chloro-5-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 64). To a solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (3.4 g, 21.36 mmol) in DMSO (70 mL) was added sodium hydride (854.27 mg, 21.36 mmol). The reaction was stirred at rt for 40min. Then 3-chloro-5-[(7S)-2-chloro-6-methyl- spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (64j, 2600 mg, 4.81 mmol) was added and the reaction was stirred at 40 °C for 1.5h. The reaction mixture was cooled to rt and diluted with H2O. It was extracted with EtOAc (50 mL*6) and concentrated to get crude product. The reaction was purified with pre-HPLC on a C18 column with a mobile phase (H2O- NH4HCO3/ACN) to afford 3-chloro-5-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 64, 2.3 g, 3.451 mmol, 67.33% yield). LCMS calculated for C35H45ClFN8O2 (M+H)+ m/z = 663.33 ; found: 663.4 1H NMR (400 MHz, CD3OD) δ 7.49 (d, J = 7.6 Hz, 1H), 7.04 – 7.24 (m, 3H), 5.27 (d, J = 53.6 Hz, 1H), 4.89 – 4.74 (m, 2H), 4.33 – 4.53 (m, 2H), 4.16 – 3.81 (m, 5H), 3.72 – 3.62 (m, 1H), 3.26 – 2.88 (m, 12H), 2.81 – 2.68 (m, 2H), 2.45 – 2.32 (m, 1H), 2.30 – 2.04 (m, 7H), 2.02 – 1.75 (m, 7H). [00789] Compound 64B.3-chloro-5-[(7R)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000274_0001
[00790] Compound 64B was isolated as minor isomer from example 21 on Regis (R,R)Whelk-O1 (250*25 mm 10 um) column on a Waters SFC 150 system (Mobile Phase A: Supercritical CO2, Mobile Phase B: CO2/EtOH[0.5%NH3(7M in MeOH)]=70/30; Flow: 100ml/min) to give faster eluting P1 (64) and slower eluting P2 (64B). LCMS calculated for C35H45ClFN8O2 (M+H)+ m/z = 663.33; found: 663.3.1H NMR (400 MHz, CD3OD) δ 7.49 (d, J = 7.6 Hz, 1H), 7.04– 7.25 (m, 3H), 5.25 (d, J = 54.8 Hz, 1H), 4.75, 4.90 (d, J = 16.8 Hz, 2H), 4.36 – 4.56 (m, 2H), 3.81 – 4.15 (m, 5H), 3.67 (d, J = 14.8 Hz, 1H), 2.89 – 3.28 (m, 12H), 2.69 – 2.80 (m, 2H), 2.32 – 2.49 (m, 1H), 2.03 – 2.31 (m, 7H), 1.71 – 2.03 (m, 7H). [00791] Compound 65.3-chloro-5-[(7S)-4'-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- indane]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000275_0001
[00792] Compound 65 was prepared similarly to that of Ex.18. LCMS calculated for C34H42ClF2N8O2 (M+H)+ m/z =667.31; found: 667.3.1H NMR (400 MHz, CD3OD) δ 7.29 (td, J = 8.0, 5.2 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.99 (t, J = 8.8 Hz, 1H), 5.26 (d, J = 54.8 Hz, 1H), 4.73 – 4.83 (m, 2H), 4.34 – 4.53 (m, 2H), 3.96 – 4.10 (m, 3H), 3.66 – 3.94 (m, 3H), 3.13 – 3.26 (m, 3H), 3.10 (s, 3H), 3.08 (s, 3H), 2.83 – 3.06 (m, 5H), 2.24 – 2.52 (m, 3H), 2.20 (s, 3H), 1.79 – 2.19 (m, 7H). [00793] Compound 66. (5R)-9-[(7S)-7'-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'- indane]-4-yl]-1,3,9-triazaspiro[4.5]decane-2,4-dione
Figure imgf000275_0002
[00794] Compound 66 was prepared similarly to that of Ex.19. LCMS calculated for C31H38F2N7O3 (M+H)+ m/z = 594.29; found: 594.4.1H NMR (400 MHz, CD3OD) δ 7.25 – 7.40 (m, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.89 – 6.99 (m, 1H), 5.26 (d, J = 52.4 Hz, 1H), 3.86 – 4.18 (m, 4H), 3.65 (d, J = 14.8Hz, 2H ), 2.93 – 3.37 (m, 9H), 2.82 – 2.91 (m, 1H), 2.42 – 2.55 (m, 1H), 1.80 – 2.32 (m, 14H). [00795] Compound 67. (5R)-9-[(7S)-4',7'-difluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- indane]-4-yl]-1,3,9-triazaspiro[4.5]decane-2,4-dione
Figure imgf000276_0001
[00796] Compound 67 was prepared similarly to that of Ex.19. LCMS calculated for C31H37F3N7O3 (M+H)+ m/z = 612.3; found: 612.3.1H NMR (400 MHz, CD3OD) δ 7.05 (td, J = 8.8, 3.6 Hz, 1H), 6.98 (td, J = 9.2, 4.0 Hz, 1H), 5.23 (d, J = 52.4 Hz, 1H), 4.05, 4.13 (d, J = 10.4 Hz, 2 H), 4.03 (d, J = 13.2 Hz, 1H), 3.92 (d, J = 13.2 Hz, 1H), 3.62, 3.68 (d, J = 14.8 Hz, 2H), 3.34 (d, J = 13.63 Hz, 1H), 3.08 – 3.23 (m, 5H), 2.94 – 3.07 (m, 3H), 2.88 (d, J = 18.0 Hz, 1H), 2.48 – 2.58 (m, 1H), 2.26 (s, 3H), 2.19 – 2.31 (m, 1H), 2.03 – 2.18 (m, 3H), 1.82 – 2.00 (m, 7H). [00797] Compound 68. (5R)-9-[(7S)-4'-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- indane]-4-yl]-1,3,9-triazaspiro[4.5]decane-2,4-dione
Figure imgf000276_0002
[00798] Compound 68 was prepared similarly to that of Ex.19. LCMS calculated for C31H38F2N7O3 (M+H)+ m/z = 594.29; found: 594.3.1H NMR (400 MHz, CD3OD) δ 7.21 – 7.39 (m, 1H), 6.92 – 7.11 (m, 2H), 5.26 (d, J = 53.6 Hz, 1H), 3.87 – 4.19 (m, 4H), 3.70 (d, J = 14.8 Hz, 2H), 3.39 (d, J = 13.2 Hz, 1H), 2.88 – 3.26 (m, 9H), 2.42 – 2.54 (m, 1H), 2.04 – 2.30 (m, 7H), 1.81 – 2.01 (m, 7H). [00799] Compound 69.3-chloro-5-[(7S)-7'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- indane]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000276_0003
[00800] Compound 69 was prepared similarly to that of Ex.19. LCMS calculated for C34H42Cl2FN8O2 (M+H)+ m/z =683.28, 685.28; found: 683.2, 685.2.1H NMR (400 MHz, CD3OD) δ 7.16 – 7.29 (m, 3H), 5.26 (d, J = 54.7 Hz, 1H), 4.77, 4.87 (d, J = 16.6 Hz, 2H), 4.34 – 4.54 (m, 2H), 4.02 – 4.11 (m, 1H), 3.98, 4.07 (d, J = 10.5 Hz, 2H), 3.84 – 3.92 (m, 1H), 3.65, 3.83 (d, J = 14.4 Hz, 2H), 3.10 – 3.30 (m, 4H), 3.09 (d, J = 6.7 Hz, 6H), 2.88 – 3.05 (m, 3H), 2.67 (d, J = 17.8 Hz, 1H), 2.33 – 2.53 (m, 2H), 2.00 – 2.34 (m, 4H), 2.22 (s, 3H), 1.78 – 1.98 (m, 4H). [00801] Compound 70. (5R)-9-[(7S)-7'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- indane]-4-yl]-1,3,9-triazaspiro[4.5]decane-2,4-dione
Figure imgf000277_0001
[00802] Compound 70 was prepared similarly to that of Ex.19. LCMS calculated for C31H38ClFN7O3 (M+H)+ m/z = 610.27, 611.27; found: 610.3, 611.3.1H NMR (400 MHz, DMSO) δ 10.77 (s, 1H), 8.68 (s, 1H), 7.15 – 7.32 (m, 3H), 5.23 (d, J = 54.0 Hz, 1H), 3.80 – 3.94 (m, 4H), 3.75 (d, J = 15.2 Hz, 1H), 3.46 (d, J = 14.4 Hz, 1H), 3.01 – 3.15 (m, 4H), 2.91 – 3.01 (m, 3H), 2.74 – 2.86 (m, 2H), 2.65 (d, J = 17.6 Hz, 1H), 2.32 – 2.44 (m, 1H), 2.11 (s, 3H), 1.85 – 2.08 (m, 5H), 1.66 – 1.85 (m, 6H). [00803] Compound 71. (5R)-9-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]-1,3,9- triazaspiro[4.5]decane-2,4-dione.
Figure imgf000277_0002
[00804] Compound 71 was prepared similarly to that of Ex.19. LCMS calculated for C32H41FN7O3 (M+H)+ m/z = 590.32; found: 590.3.1H NMR (400 MHz, CD3OD) δ 7.45 – 7.57 (m, 1H), 7.05 – 7.26 (m, 3H), 5.23 (d, J = 52.0 Hz, 1H), 3.90 – 4.19 (m, 4H), 3.73 (d, J = 15.0 Hz, 2H), 3.38 (d, J = 13.2 Hz, 1H), 2.89 – 3.24 (m, 7H), 2.71 – 2.80 (m, 2H), 1.75 – 2.29 (m, 17H). [00805] Compound 72.5-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]-N,N- dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000278_0001
[00806] Compound 72 was prepared similarly to that of Ex.19. LCMS calculated for C35H46FN8O2 (M+H)+ m/z = 629.37; found: 629.3.1H NMR (400 MHz, DMSO) δ 7.45 (d, J = 7.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.13 (td, J = 7.6, 1.2 Hz, 1H), 7.07 (d, J = 6.4 Hz, 1H), 6.51 (s, 1H), 5.24 (d, J = 54.0 Hz, 1H), 4.79, 4.72 (d, J = 16.4 Hz, 2H), 4.47 (t, J = 5.2 Hz, 2H), 3.77 – 4.00 (m, 4H), 3.61 – 3.73 (m, 2H), 3.24 (s, 3H), 2.96 – 3.10 (m, 3H), 2.93 (s, 3H), 2.66 – 2.90 (m, 5H), 2.03 – 2.22 (m, 2H), 2.00 (s, 3H), 1.59 – 1.98 (m, 10H). [00807] Example 22. Exemplary synthesis of 5-[5-[(7S)-7'-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-3-methyl- 1,2,4-oxadiazole Compound 73.
Figure imgf000278_0002
[00808] Step 1. Synthesis of 3-methyl-5-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin- 2-yl)-1,2,4-oxadiazole (73a). To a solution of N-hydroxyacetamidine (375.66 mg, 5.07 mmol) and 3Å molecular sieves in THF (5 mL) were added NaH (76.06 mg, 3.17 mmol), The mixture was stirred at R.T. for 15 min. ethyl 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxylate (Int-1c, 500 mg, 1.27 mmol) was added to the mixture. The mixture was stirred at 25 °C for 3 h. The mixture was filtered over celite and concentrated. The crude product was purified by flash chromatography (eluted with CH3CN in H2O from 5.0% to 95%) to afford the desired product 3-methyl-5-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepin-2-yl)-1,2,4-oxadiazole (73a, 230 mg, 1.05 mmol, 82.75 %yield) as a yellow solid. LCMS calculated for C10H13N5O (M+H)+ m/z =220.1, found: 220.1. [00809] Step 2. Synthesis of 5-[5-[(7S)-2-chloro-7'-fluoro-6-methyl-spiro[5,8- dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]-3-methyl-1,2,4-oxadiazole (73c). The mixture of (7S)-2,4-dichloro-7'- fluoro-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-indane] (73b, prepared similarly as 64i, 50 mg, 0.15 mmol), 3-methyl-5-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2- yl)-1,2,4-oxadiazole (73a, 34.03 mg, 0.16 mmol) and DIEA (0.05 mL, 0.3 mmol) in DMSO (1 mL) was stirred at rt for 68 h. The reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated and purified by prep-HPLC (0.1% NH4HCO3) to afford to afford 5-[5-[(7S)-2-chloro-7'-fluoro-6-methyl-spiro[5,8- dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]-3-methyl-1,2,4-oxadiazole (73c, 50 mg, 0.0960 mmol, 64.92 %yield) as a white solid. LCMS calculated for C26H27ClFN8O (M+H)+ m/z = 521.20, 523.19; found: 521.1, 523.1 [00810] Step 3. Synthesis of 5-[5-[(7S)-7'-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-3-methyl-1,2,4-oxadiazole (Compound 73). To a solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (152.79 mg, 0.96 mmol) in DMSO (3 mL) was added NaH (38.39 mg, 0.96 mmol) under N2 and stirred 20 min, then the mixture was added 5-[5-[(7S)-2-chloro-7'-fluoro-6-methyl- spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]-3-methyl-1,2,4-oxadiazole (73c, 50 mg, 0.1 mmol) and stirred at 40 °C for 1 h, The reaction mixture was quenched with water , and extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 3% to 12% MeOH/DCM) and purified by prep-HPLC (0.1% NH4HCO3) to afford 5- [5-[(7S)-7'-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6- methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-3-methyl-1,2,4-oxadiazole (Compound 73, 32 mg, 0.0487 mmol, 50.76 %yield) as a white solid. LCMS calculated for C34H40F2N9O2 (M+H)+ m/z = 644.33, 645.33; found: 644.3, 645.3.1H NMR (400 MHz, CD3OD) δ = 7.27 – 7.35 (m, 1H), 7.10 (d, J=7.6, 1H), 6.99 (s, 1H), 6.91 – 6.97 (m, 1H), 5.24 (d, J=53.1, 1H), 4.50 – 4.66 (m, 4H), 3.97 – 4.11 (m, 4H), 3.64 – 3.76 (m, 2H), 3.05 – 3.22 (m, 5H), 2.91 – 3.04 (m, 2H), 2.83 (d, J=18.0, 1H), 2.45 – 2.56 (m, 1H), 2.41 (s, 3H), 2.18 – 2.35 (m, 5H), 2.09 – 2.18 (m, 2H), 2.00 – 2.08 (m, 1H), 1.75 – 1.99 (m, 4H). [00811] Compound 74.5-[5-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-3-methyl-1,2,4-oxadiazole
Figure imgf000280_0001
[00812] Compound 74 was prepared similarly to that of Ex.22. LCMS calculated for C35H43FN9O2 (M+H)+ m/z = 640.25; found: 640.3.1H NMR (400 MHz, CD3OD) δ 7.49 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.14 (td, J = 7.6, 1.2 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.99 (s, 1H), 5.25 (d, J = 54.8 Hz, 1H), 4.86 – 4.96 (m, 2H), 4.50 – 4.67 (m, 2H), 3.96 – 4.12 (m, 4H), 3.70 – 3.86 (m, 2H), 3.12 – 3.24 (m, 3H), 2.89 – 3.04 (m, 3H), 2.70 – 2.80 (m, 2H), 2.41 (s, 3H), 2.13 – 2.37 (m, 3H), 2.12 (s, 3H), 1.73 – 2.08 (m, 9H). [00813] Example 23. Exemplary synthesis of 3-chloro-5-[6'-(difluoromethyl)-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine- 7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 75)
Figure imgf000280_0002
[00814] Step 1. Synthesis of 5-(6'-bromo-2-methylsulfanyl-spiro[5,8-dihydropyrano[4,3- d]pyrimidine-7,1'-indane]-4-yl)-3-chloro-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide (75b). To the solution of 6'-bromo-4-chloro-2-methylsulfanyl- spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane] (75a, 600 mg, 1.51 mmol) DIEA (0.79 mL, 4.53 mmol) and 3-chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide (366.15 mg, 1.51 mmol) in DMF (6 mL) and stirred at 100 °C for 2 h. The mixture was extracted with water (20 mL) and EtOAc (3x10 mL), washed with brine (10 mL), dried with Na2SO4, concentrated. The crude product was purified by flash chromatography (eluted with CH3CN in H2O from 5.0% to 50%) to afford 5-(6'-bromo-2- methylsulfanyl-spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl)-3-chloro-N,N- dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (75b, 800 mg,1.3246 mmol, 87.80% yield) as yellow solid. LCMS calcld for C26H28BrClN6O2S (M+H)+ m/z = 605.2, found: 605.2. [00815] Step 2. Synthesis of 3-chloro-N,N-dimethyl-5-(2-methylsulfanyl-6'-vinyl-spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl)-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide (75c). The mixture of 5-(6'-bromo-2-methylsulfanyl-spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl)-3-chloro-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (75b, 500 mg, 0.83 mmol), K2CO3 (343 mg, 2.48 mmol), Pd(Dppf)Cl2 (60.52mg, 0.08 mmol) and potassium;trifluoro(vinyl)boranuide (277 mg, 2.07 mmol) was added in DMSO (10mL) and stirred at 100 °C for 16 h under Ar. The crude product was purified by flash chromatography (eluted with CH3CN in H2O from 5.0% to 95%) to afford 3-chloro-N,N-dimethyl-5-(2-methylsulfanyl-6'-vinyl-spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl)-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide (75c, 360mg, 0.653mmol, 78.9% yield) as a yellow solid. LCMS calcld for C28H31ClN6O2S (M+H)+ m/z = 551.2, found: 551.2. [00816] Step 3. Synthesis of 3-chloro-5-(6'-formyl-2-methylsulfonyl-spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl)-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (75d). To a solution of 3-chloro-N,N- dimethyl-5-(2-methylsulfanyl-6'-vinyl-spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4- yl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (75c, 320 mg, 0.58 mmol), Potassium osmate(VI) dihydrate (9.04 mg, 0.03 mmol) and Sodium Periodate (496.79 mg, 2.32 mmol) was added in THF (4mL) and Water (1mL) at 25 °C. The mixture was stirred at 50 °C for 16 h. The crude product was purified by flash chromtography (eluted with CH3CN in H2O from 5.0% to 95%) to afford 3-chloro-5-(6'-formyl-2-methylsulfonyl-spiro[5,8-dihydropyrano[4,3- d]pyrimidine-7,1'-indane]-4-yl)-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine- 2-carboxamide (75d, 120 mg,0.205 mmol, 35.3% yield) as a white solid. LCMS calcld for C27H29ClN6O5S (M+H)+ m/z = 585.3, found: 585.3. [00817] Step 4. Synthesis of 3-chloro-5-[6'-(difluoromethyl)-2-methylsulfonyl-spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (75e). To a solution of 3-chloro-5-(6'- formyl-2-methylsulfonyl-spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl)-N,N- dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (75d, 100 mg, 0.17 mmol), and DAST (0.23 mL, 1.71 mmol) was added in DCM (1mL) at 0 °C. The mixture was stirred at 25 °C for 16 h. The mixture was quenched with NH4Cl (5 mL) , then the mixture was extracted with DCM (3x5 mL) and water (10 mL), dried over Na2SO4, concentrated to afford the crude of 3-chloro-5-[6'-(difluoromethyl)-2-methylsulfonyl-spiro[5,8-dihydropyrano[4,3- d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine- 2-carboxamide (75e, 100 mg, 0.165 mmol, 96.38% yield) was obtained as a yellow solid. LCMS calcld for C27H29ClF2N6O4 (M+H)+ m/z = 607.3, found: 607.3. [00818] Step 5. Synthesis of 3-chloro-5-[6'-(difluoromethyl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]- N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 75). To a solution of NaH (13.84 mg, 0.35 mmol) and [(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methanol (55.07 mg, 0.35 mmol) in DMF (1 mL) and stirred at 25 °C for 10 min, then 3-chloro-5-[6'-(difluoromethyl)-2-methylsulfonyl-spiro[5,8-dihydropyrano[4,3- d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine- 2-carboxamide (75e, 70 mg, 0.12 mmol) was added at 25 °C. The mixture was stirred at 25 °C for 10 min. The mixture was extracted with water (10 mL) and EA (3x15 mL), then washed with brine (10 mL), dried over Na2SO4, concentrated. The crude product was purified by Prep-HPLC (eluted with CH3CN in H2O (0.1 % FA) from 5.0% to 95%) to afford 3-chloro-5-[6'- (difluoromethyl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8- dihydropyrano[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide;formic acid (Compound 75, 25.1 mg,0.035 mmol, 30.36% yield) as a white solid. LCMS calcld for C34H39ClF3N7O3 (M+H)+ m/z = 686.2, found: 686.2.1H NMR (400 MHz, CD3OD) δ 7.45 (dd, J = 18.7, 7.8 Hz, 2H), 7.31 (s, 1H), 6.72 (t, J = 56.3 Hz, 1H), 5.42 – 5.15 (m, 1H), 4.83 – 4.69 (m, 2H), 4.61 – 4.52 (m, 1H), 4.47 – 4.33 (m, 2H), 4.14 – 4.04 (m, 2H), 3.94 – 3.75 (m, 2H), 3.27 – 3.11 (m, 4H), 3.09 (d, J = 8.1 Hz, 6H), 3.04 – 2.88 (m, 4H), 2.42 – 1.82 (m, 11H). [00819] Example 24. Exemplary synthesis of 3-cyano-5-[(7S)-7'-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine- 2-carboxamide [00820] Compound 76.
Figure imgf000283_0001
[00821] Step 1. Synthesis of 3-iodo-N,N-dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (76a). To a solution of N,N-dimethyl-5- (2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Int-1e, 200 mg, 0.51 mmol) in HOAc (2 mL, 34.94 mmol) was added N-Iodosuccinimide (228.74 mg, 1.02 mmol). The mixture was stirred at 80 °C for 2h. The mixture was diluted with water , extracted with DCM, washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 5% MeOH/DCM) to afford 3-iodo-N,N- dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carboxamide (76a, 264 mg, 0.5084 mmol, 100% yield) as a yellow solid. LCMS calcld for C16H19IN5O5S (M+H)+ m/z = 520.02, found:520.1. [00822] Step 2. Synthesis of 3-cyano-N,N-dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (76b). The mixture of 3-iodo-N,N- dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carboxamide (76a, 630 mg, 1.21 mmol), and CuCN (539.85 mg, 6.07 mmol) in DMF (1 mL) was sealed and stirred at 135 °C for 20 h. After completion, the reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 5% MeOH/DCM) to afford 3-cyano-N,N-dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide (76b, 340 mg, 0.8126 mmol, 66.98% yield) as a white solid. LCMS calcld for C17H19N6O5S (M+H)+ m/z =419.12; found: 419.2. [00823] Step 3. Synthesis of 3-cyano-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide (76c). To a solution of 3-cyano-N,N-dimethyl-5-(2- nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (76b, 340mg, 0.81mmol) ,4-methoxybenzenethiol (341.76 mg, 2.44 mmol) and cesium carbonate (1056.33 mg, 3.25 mmol) in MeCN (4 mL). The mixture was stirred at 20 °C for 2 h. The mixture was filtered, concentrated and the crude product was purified by silica gel chromatography (eluted with MeOH in DCM from 3% to 10%) to afford 3-cyano-N,N-dimethyl- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (76c, 164 mg,0.703 mmol, 86.52% yield) as a white solid. LCMS calcld for C11H16N5O (M+H)+ m/z = 234.14, found: 234.1. [00824] Step 4. Synthesis of 5-[(7S)-2-chloro-7'-fluoro-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-indane]-4-yl]-3-cyano-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide (76d). The mixture of (7S)-2,4-dichloro-7'-fluoro-6-methyl- spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-indane] (73b, 70 mg, 0.21 mmol), 3-cyano-N,N- dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (53.11 mg, 0.23 mmol) and DIEA (0.14 mL, 0.83 mmol) in DMSO (1.5 mL) was stirred at 30 °C for 20 h. The reaction mixture was filtered and purified by prep-HPLC (0.1% NH4HCO3) to afford to afford 5-[(7S)-2-chloro-7'-fluoro-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4- yl]-3-cyano-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (62 mg, 0.116 mmol, 55.99% yield) as a white solid. LCMS calculated for C27H29ClFN8O (M+H)+ m/z = 535.22; found: 535.3. [00825] Step 5. The mixture of 5-[(7S)-2-chloro-7'-fluoro-6-methyl-spiro[5,8- dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-3-cyano-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (50 mg, 0.09 mmol),[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (22.32 mg, 0.14 mmol), Pd2dba3 (12.84 mg, 0.01 mmol), Ruphos (13.08 mg, 0.03 mmol) and cesium carbonate (91.12 mg, 0.28 mmol) in Toluene (2 mL) was charged with N2 and sealed. The mixture was stirred at 110 °C for 5h. LCMS showed OK. The mixture was diluted with water, extracted with EtOAc, washed with brine , dried over Na2SO4, concentrated and purified by prep-HPLC(0.1%NH4HCO3) to afford 3-cyano- 5-[(7S)-7'-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-methyl- spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (39.09 mg, 0.0587 mmol, 52.99% yield) as a light yellow solid. LCMS calculated for C35H42F2N9O2 (M+H)+ m/z = 658.35; found: 658.5. 1H NMR (400 MHz, CD3OD) δ 7.31 (td, J = 8.0, 5.2 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.93 (dd, J = 10.0, 8.4 Hz, 1H), 5.29 (d, J = 53.8 Hz, 1H), 4.87 – 4.97 (m, 2H), 4.37 – 4.57 (m, 2H), 3.89 – 4.12 (m, 4H), 3.66, 3.77 (d, J = 14.4 Hz, 2H), 3.32 (s, 3H), 3.12 – 3.28 (m, 4H), 3.10 (s, 3H), 2.94 – 3.08 (m, 3H), 2.86 (d, J = 18.0 Hz, 1H), 2.29 – 2.55 (m, 3H), 2.27 (s, 3H), 2.03 – 2.22 (m, 3H), 1.83 – 1.99 (m, 4H). [00826] Compound 77.3-cyano-5-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000285_0001
[00827] Compound 77 was prepared similarly to that of Ex.23. LCMS calculated for C36H45FN9O2 (M+H)+ m/z = 654.37; found: 654.2.1H NMR (400 MHz, CD3OD) δ 7.50 (dd, J = 8.0, 1.2 Hz, 1H), 7.22 (td, J = 7.4, 1.6 Hz, 1H), 7.14 (td, J = 7.4, 1.2 Hz, 1H), 7.08 (dd, J = 7.6, 1.2 Hz, 1H), 5.28 (d, J = 53.6 Hz, 1H), 4.87 – 4.98 (m, 2H), 4.32 – 4.62 (m, 2H), 4.11 (d, J = 10.8 Hz, 1H), 3.93 – 4.06 (m, 2H), 3.83 – 3.92 (m, 2H), 3.70 (d, J = 14.8 Hz, 1H), 3.32 (s, 3H), 3.12 – 3.26 (m, 3H), 3.10 (s, 3H), 2.90 –3.07 (m, 3H), 2.71 – 2.80 (m, 2H), 2.13 – 2.44 (m, 4H), 2.11 (s, 3H), 1.71 – 2.08 (m, 8H). [00828] Compound 78. 3-chloro-5-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000285_0002
[00829] Compound 78 was prepared similarly to that of Ex. 21. LCMS calculated for C33H40ClFN7O3, (M+H)+ m/z = 636.29, 638.29; found: 636.3, 638.3. 1H NMR (400 MHz, DMSO) δ = 7.46 (d, J=7.7 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 7.12 (td, J=7.4, 1.2 Hz, 1H), 7.07 (d, J=6.8 Hz, 1H), 5.23 (d, J=53.4 Hz, 1H), 4.73 (d, J=16.4 Hz, 2H), 4.34 – 4.53 (m, 2H), 3.87 – 3.98 (m, 1H), 3.83 (s, 2H), 3.68 – 3.80 (m, 2H), 3.60 (d, J=14.9 Hz, 1H), 2.86 – 3.08 (m, 4H), 2.65 – 2.83 (m, 4H), 2.17 – 2.32 (m, 1H), 1.94 – 2.12 (m, 6H), 1.77 – 1.94 (m, 4H), 1.62 – 1.77 (m, 4H). [00830] Example 25. Exemplary synthesis of 3-chloro-5-[(7S)-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-tetralin]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-amine (Compound 79).
Figure imgf000286_0001
[00831] To a sealed vial was charged a solution of 3-chloro-5-[(7S)-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-tetralin]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (Compound 78, 30 mg, 0.05 mmol) in 1,4-Dioxane (1 mL), followed by the addition of azido(phenoxy)phosphoryl]oxybenzene (19.47 mg, 0.07 mmol) and t-BuOH (59.42 mg, 0.8 mmol) under N2. The mixture was heated at 110 °C for 2 hours. The reaction solution was cooled down to rt, and EtOAc was added. The mixture was washed successively with H2O, NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by prep-HPLC to afford 3-chloro-5-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-methyl- spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-amine (Compound 79, 8.0 mg, 0.0132 mmol, 28.05% yield) as a white solid. LCMS calculated for C32H41ClFN8O (M+H)+ m/z = 607.31, 609.31; found: 607.3, 609.31. 1H NMR (400 MHz, CD3OD) δ = 7.49 (d, J=7.1 Hz, 1H), 7.20 (td, J=7.5, 1.8 Hz, 1H), 7.14 (td, J=7.4, 1.3 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 5.26 (d, J=54.4 Hz, 1H), 4.68 (d, J=16.6 Hz, 2H), 3.78 –4.23 (m, 7H), 3.67 (d, J=14.9 Hz, 1H), 3.11 – 3.28 (m, 3H), 2.88 – 3.07 (m, 3H), 2.70 – 2.80 (m, 2H), 2.23 – 2.37 (m, 1H), 1.70 – 2.21 (m, 14H). [00832] Compound 80. 4-[[1-[[(7S)-6-methyl-4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl]spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-2- yl]oxymethyl]cyclopropyl]methyl]morpholine
Figure imgf000287_0001
[00833] Compound 80 was prepared similarly to that of Ex. 21. LCMS calculated for C32H45N6O2 (M+H)+ m/z =545.4; found: 545.3.1H NMR (400 MHz, CD3OD) δ 7.50 (d, J = 7.6 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.08 (d, J = 6.8 Hz, 1H), 4.14 – 4.33 (m, 3H), 3.56 – 3.77 (m, 9H), 3.43 (d, J = 12.0 Hz, 1H), 2.86 – 3.09 (m, 3H), 2.75 (d, J = 5.2 Hz, 2H), 2.47 (s, 4H), 2.38 (s, 2H), 2.09 (s, 3H), 1.62 – 2.04 (m, 8H), 0.63 (t, J = 5.6 Hz, 2H), 0.45 (t, J = 5.6 Hz, 2H). [00834] Intermediate 3.
Figure imgf000287_0002
[00835] Step 1. Synthesis of N,N-dimethyl-5-(2-nitrophenyl)sulfonyl-3-(2- trimethylsilylethynyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide. To a solution of 3-iodo-N,N-dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide (76a, 500 mg, 0.96 mmol), Trimethylsilylacetylene (0.71 mL, 5.09 mmol) and Triethylamine (292.28 mg, 2.89 mmol) in DMF (10 mL) was added Bis(Triphenylphosphine)Palladium(II) Chloride (135.16 mg, 0.19 mmol) and Copper (I) Iodide (36.67 mg, 0.19 mmol) under N2. The mixture was stirred at 45°C for 20 h. The reaction solution was filtrated, washed by DCM/MeOH=10:1 and concentrated. The residue was purified by flash chromatography (DCM/MeOH=20:1) to give N,N-dimethyl-5-(2-nitrophenyl)sulfonyl-3-(2- trimethylsilylethynyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Int-3a, 345.5 mg, 0.529 mmol, 54.97% yield). LCMS calculated for C21H28N5O5SiS (M+H)+ m/z =490.15; found: 490.0. [00836] Step 2. Synthesis of N,N-dimethyl-3-(2-trimethylsilylethynyl)-5,6,7,8-tetrahydro- 4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. To a solution of N,N-dimethyl-5-(2- nitrophenyl)sulfonyl-3-(2-trimethylsilylethynyl)-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide (Int-3a, 350 mg, 0.54 mmol), 4-methoxybenzenethiol (225.5 mg, 1.61 mmol) in CH3CN (3 mL) was added cesium carbonate (696.97 mg, 2.14 mmol). The mixture was stirred at 20°C for 2 h. The mixture was filtered, concentrated and the crude product was purified by pre-HPLC on a C18 column with a mobile phase (H2O-NH4HCO3/CH3CN) to afford N,N-dimethyl-3-(2-trimethylsilylethynyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine- 2-carboxamide (Int-3b, 101 mg, 0.331 mmol, 61.88% yield). LCMS calcld for C15H25N4OSi (M+H)+ m/z = 305.17, found: 305.2. [00837] Step 3. Synthesis of 3-ethynyl-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide. To a solution of N,N-dimethyl-3-(2-trimethylsilylethynyl)- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Int-3b, 101 mg, 0.33 mmol) in Methanol (5 mL) was added K2CO3 (105.29 mg, 0.76 mmol). The mixture was stirred at 20 °C for 1h. The mixture was filtered, and the filtrate was concentrated and the residue was purified by flash chromatography (DCM/MeOH) to give 3-ethynyl-N,N-dimethyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Intermediate 3, 75 mg, 0.323 mmol, 97.33% yield). LCMS calculated for C12H17N4O (M+H)+ m/z = 233.13 ; found: 233.3. [00838] Compound 81. 3-ethynyl-5-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000288_0001
[00839] Compound 81 was prepared similarly to that of Ex. 21 using intermediate 3. LCMS calculated for C37H46FN8O2 (M+H)+ m/z = 653.36; found: 653.3. 1H NMR (400 MHz, CD3OD) δ 7.45 – 7.53 (m, 1H), 7.04 – 7.24 (m, 3H), 5.26 (d, J = 54.4 Hz, 1H), 4.71 – 4.90 (m, 2H), 4.44 – 4.54 (m, 1H), 4.30 – 4.40 (m, 1H), 3.80 – 4.16 (m, 6H), 3.66 (d, J = 14.8 Hz, 1H), 2.89 – 3.25 (m, 12H), 2.71– 2.80 (m, 2H), 2.36 – 2.51 (m, 1H), 2.05 – 2.32 (m, 7H), 1.73 – 2.03 (m, 7H). [00840] Intermediate 4.
Figure imgf000288_0002
[00841] Step 1. Synthesis of [5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]methanol (Int-4a). To a solution of ethyl 5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate (Int-1c 1500 mg, 3.8 mmol) in THF (15 mL) was added 1M DABAL-H in hexane (11.41 mL, 11.41 mmol) at -68 °C under argon. The mixture was stirred at 25 °C for 2 h. The reaction was quenched with water and isopropyl alcohol (1:1,12mL) and extracted with EtOAc (50 ml x 3) and concentrated. The crude product [5-(2- nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]methanol (Int-4a, 850 mg, 2.39 mmol, 62.79 %yield) was carried over without purification. LCMS calcld for C14H17N4O5S (M+H)+ m/z =353.1, found:353.1. [00842] Step 2. Synthesis of 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carbaldehyde (Int-4b). To a solution of [5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]methanol (Int-4a, 850 mg, 2.41 mmol) in DMSO (8 mL) was added IBX (514.6 mg, 3.62 mmol) at 25 °C under argon. The mixture was stirred at 25 °C for 16 h. The mixture was filtered to afford a crude solution. The crude product was purified by flash chromatography (eluted with CH3CN in H2O from 50% to 55%). 5-(2- nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbaldehyde (Int-4b, 570 mg, 1.59 mmol, 66.10 %yield) was obtained as a white solid. LCMS calcld for C14H15N4O5S(M+H)+ m/z =351.1 , found: 351.1. [00843] Step 3. Synthesis of 2-(1-methylbenzimidazol-2-yl)-5-(2-nitrophenyl)sulfonyl- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine (Int-4c). The solution of 5-(2- nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbaldehyde (Int-4b, 250 mg, 1 mmol) and N2-methylbenzene-1,2-diamine (244.34 mg, 2 mmol) in DMF (2 mL) was stirred at 100 °C for 18 h. The mixture was extracted with EtOAc and water, washed with brine and dried over Na2SO4, concentrated and purified by silica gel chromatography (DCM: MeOH= 50:1) to get the 2-(1-methylbenzimidazol-2-yl)-5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine (Int-4c, 320 mg, 0.707 mmol, 70.72%yield). LCMS calcld for C21H21N6O4S (M+H)+ m/z = 453.49, found: 453.2. [00844] Step 4. Synthesis of 2-(1-methylbenzimidazol-2-yl)-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine (Intermediate 4). A solution of Cs2CO3 (230.42 mg, 0.71 mmol), 2-(1-methylbenzimidazol-2-yl)-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine (Int-4c, 160 mg, 0.35 mmol) and 4-Methoxythiophenol (74.36 mg, 0.53 mmol) in CH3CN (5 mL) was stirred at 25 °C for 3h. The mixture was filtered, and the solvent was removed. The residue was purified by silica gel chromatography (DCM: MeOH=11: 1) to give 2- (1-methylbenzimidazol-2-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine (Intermediate 4, 70 mg, 0.262 mmol, 74.05%yield). LCMS calcld for C15H18N5 (M+H)+ m/z = 268.33, found: 268.3. [00845] Compound 82. (7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-6-methyl-4-[2-(1-methylbenzimidazol-2-yl)-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-5-yl]spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]
Figure imgf000290_0001
[00846] Compound 82 was prepared similarly to that of Ex. 21 using intermediate 4. LCMS calculated for C40H47FN9O (M+H)+ m/z = 688.38; found: 688.3. 1H NMR (400 MHz, CD3OD) δ 7.61 – 7.68 (m, 1H), 7.45 – 7.52 (m, 2H), 7.23 – 7.33 (m, 2H), 7.03 – 7.21 (m, 3H), 6.97 (s, 1H), 5.14 (d, J = 52.4 Hz, 1H), 4.80 – 4.95 (m, 2H), 4.50 – 4.67 (m, 2H), 3.92 – 4.18 (m, 7H), 3.76, 3.85 (d, J = 14.8 Hz, 2H), 2.85 – 3.15 (m, 6H), 2.67 – 2.78 (m, 2H), 2.29 – 2.42 (m, 1H), 1.92 – 2.22 (m, 9H), 1.69 – 1.90 (m, 5H). [00847] Compound 83. (7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-4-[2-(4-fluoro-1-methyl-benzimidazol-2-yl)-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-5-yl]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]
Figure imgf000290_0002
[00848] Compound 83 was prepared similarly to Compound 82. LCMS calculated for C40H46F2N9O (M+H)+ m/z = 706.38; found: 706.3. 1H NMR (400 MHz, CD3OD) δ 7.49 – 7.51 (m, 1H), 7.35 – 7.37 (m, 1H), 7.25 – 7.30 (m, 1H), 7.17 – 7.21 (m, 1H), 7.11 – 7.15 (m, 1H), 7.07 – 7.09 (m, 1H), 7.04 (s, 1H), 6.98 – 7.03 (m, 1H), 5.20 (d, J = 53.6 Hz, 1H), 4.90 – 4.96 (m, 2H), 4.56 – 4.68 (m, 2H), 4.19 (s, 3H), 3.97 – 4.14 (m, 4H), 3.78, 3.86 (d, J = 14.4 Hz, 2H), 2.91 – 3.22 (m, 6H), 2.75 – 2.78 (m, 2H), 2.23 – 2.41 (m, 2H), 2.14 (s, 3H), 1.70 – 2.10 (m, 10H). [00849] Compound 84. (7S)-4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-tetralin]
Figure imgf000291_0001
[00850] Compound 84 was prepared similarly to that of Ex. 21. LCMS calculated for C31H42FN6O (M+H)+ m/z =533.3; found: 533.3.1H NMR (400 MHz, CD3OD) δ 7.49 (d, J = 7.6 Hz, 1H), 7.06 – 7.23 (m, 3H), 5.17 – 5.36 (m, 1H), 4.21 (d, J = 12.0 Hz, 1H), 4.03, 4.15 (d, J =10.4 Hz, 2H), 3.54 – 3.77 (m, 5H), 3.42 (d, J = 12.0 Hz, 1H), 3.13 – 3.28 (m, 3H), 2.87 – 3.09 (m, 4H), 2.71 – 2.80 (m, 2H), 2.11 – 2.33 (m, 2H), 2.09 (s, 3H), 1.67 – 2.07 (m, 12H). [00851] Compound 85. (1R,5S)-3-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-4-yl]-3-azabicyclo[3.2.1]octan-8-amine
Figure imgf000291_0002
[00852] Compound 85 was prepared similarly to that of Ex. 21 using intermediate 3. LCMS calculated for C32H44FN6O (M+H)+ m/z =547.4; found: 547.5. 1H NMR (400 MHz, DMSO) δ 7.46 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 7.2 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 5.24 (d, J = 53.6 Hz, 1H), 3.97 – 4.09 (m, 1H), 3.79, 3.93 (d, J =10.0 Hz, 2H), 3.46 – 3.66 (m, 4H), 3.15 – 3.23 (m, 1H), 3.03 – 3.11 (m, 3H), 2.61 – 3.02 (m, 8H), 2.04 – 2.12 (m, 3H), 1.98 (s, 3H), 1.98-2.01 (m, 1H), 1.59 – 1.95 (m, 11H), 1.30 – 1.43 (m, 1H). [00853] Example 26. Exemplary synthesis of [(1R,5S)-3-[(7S)-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-tetralin]-4-yl]-3-azabicyclo[3.2.1]octan-8-yl]cyanamide (Compound 86).
Figure imgf000291_0003
[00854] To a solution of (1R,5S)-3-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-4-yl]-3-azabicyclo[3.2.1]octan-8-amine (Compound 85, 5 mg, 0.01 mmol) in THF (0.3 mL) were added BrCN (0.93 mg, 0.01 mmol) and Et3N (1.5 uL, 0.01mmol) at -20 °C. The reaction was stirred at [00855] -20 °C for 2h. Then the mixture was filtered and purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase: H2O (0.1% NH4HCO3) / CH3CN at flow rate of 35 mL/min to afford [(1R,5S)-3-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]-3- azabicyclo[3.2.1]octan-8-yl]cyanamide (Compound 86, 2.22 mg, 0.0035 mmol, 39.58% yield) as a white solid. LCMS calculated for C33H43FN7O (M+H)+ m/z =572.4; found: 572.5. [00856] 1H NMR (400 MHz, DMSO) δ 7.46 (d, J = 7.6 Hz, 1H), 7.20 (t, J = 6.8 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H), 6.87 (d, J = 2.8 Hz, 1H), 5.25 (d, J = 55.6 Hz, 1H), 3.99 – 4.08 (m, 1H), 3.91 – 3.97 (m, 1H), 3.79 – 3.85 (m, 1H), 3.54 – 3.64 (m, 4H), 3.20 – 3.24 (m, 1H), 3.04 – 3.10 (m, 1H), 2.64 – 3.02 (m, 8H), 1.42 – 2.12 (m, 19H). [00857] Intermediate 5. Synthesis of 3-(3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepin-2-yl)-5-methyl-1,2,4-oxadiazole
Figure imgf000292_0001
[00858] Step 1. Synthesis of 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide (Int-5a). To a solution of 5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (Int-1d, 870 mg, 2.37 mmol), DIEA (1.65 mL, 9.5 mmol) and HATU (1354.48 mg, 3.56 mmol) in DMF (2 mL) was added NH4Cl (171.13 mg, 2.85 mmol). The reaction was stirred at 30 °C for 2h. The mixture was diluted with DCM (30 x 2 mL), washed with water (40 mL) and brine (40 mL), dried over Na2SO4. The solvent was removed and the residue was purified by flash chromatography (eluted with CH3CN in H2O from 5.0% to 95%) to afford 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide (Int-5a, 760 mg, 2.08 mmol, 87.59 %yield) as a yellowish solid. LCMS calcld for C14H16N5O5S (M+H)+ m/z =366.0 , found: 366.0. [00859] Step 2. Synthesis of 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carbonitrile (Int-5b). To a solution of 5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Int-5a, 1.5g, 4.11 mmol) and Pyridine (1 mL, 12.32 mmol) in THF (10mL) was added TFAA (2586.98 mg, 12.32 mmol) slowly at 25°C. The mixture was stirred at 25°C for 48 h. The mixture was quenched with H2O (20 mL), extracted with EtOAc (20 x 3 mL), dried over Na2SO4, concentrated. The crude product was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 10% to 90%) to afford 5- (2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonitrile (Int-5b, 0.8 g, 2.303 mmol, 56.10% yield) as a yellow solid. LCMS calcld for C14H14N5O4S (M+H)+ m/z =348.07, found: 348.0. [00860] Step 3. Synthesis of 3-chloro-5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonitrile (Int-5c). To a solution of 5-(2- nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonitrile (500 mg, 1.44 mmol) in CH3CN (5 mL) were added NCS (192.21 mg, 1.44 mmol). The mixture was stirred at 60 °C for 4h. The mixture was quenched with H2O (10 mL), extracted with EtOAc (30 mL), dried over Na2SO4, concentrated. The crude product was purified by flash chromatography (eluted with EtOAc in petroleum ether from 10% to 90%). The product 3-chloro-5-(2- nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonitrile (Int-5c, 400 mg, 1.05 mmol, 72.78% yield) was obtained as a white solid. LCMS calcld for C14H13ClN5O4S (M+H)+ m/z = 382.1, found:382.0. [00861] Step 4. Synthesis of 3-chloro-N-hydroxy-5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamidine (Int-5d). To a solution of 3-chloro-5- (2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonitrile (Int-5c, 400 mg, 105mmol) and K2CO3 (433.75 mg, 3.14 mmol) in Ethanol (2 mL) was added NH2OH.HCl (144.58 mg, 2.1 mmol). The reaction was stirred at 80 °C for 12 h. The mixture was cooled to rt, filtered, and washed with water (10ml) to give crude product 3-chloro-N-hydroxy-5-(2- nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamidine (Int-5d, 183 mg, 0.441 mmol, 42.11% yield) as a white solid. LCMS calcld for C14H16ClN6O5S (M+H)+ m/z = 415.0, found:.415.2. [00862] Step 5. Synthesis of 3-[3-chloro-5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-5-methyl-1,2,4-oxadiazole (Int-5e). To a solution of 3-chloro-N-hydroxy-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine- 2-carboxamidine (183 mg, 0.44 mmol) in Acetic acid (2 mL) were added Acetic anhydride (Int- 5d, 67.56 mg, 0.66 mmol). The reaction was stirred at 100 °C for 16h. The mixture was filtered to give crude product. The crude product was purified by flash chromatography (eluted with CH3CN in H2O from 5.0% to 43%). The product 3-[3-chloro-5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-5-methyl-1,2,4-oxadiazole (Int-5e,163 mg, 0.371 mmol, 84.19% yield) was obtained as a white solid. LCMS calcld for C16H16ClN6O5S(M+H)+ m/z = 439.1, found: 439.2. [00863] Step 6. Synthesis of 3-(3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepin-2-yl)-5-methyl-1,2,4-oxadiazole (Intermediate 5). A solution of 3-[3-chloro-5- (2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-5-methyl-1,2,4- oxadiazole (Int-5e, 150 mg, 0.34 mmol), 4-methoxybenzenethiol (0.13 mL, 1.03 mmol) and cesium carbonate (444.34 mg, 1.37 mmol) in CH3CN (4 mL) was stirred at 20 °C for 1 h. The mixture was filtrated and purified by prep-HPLC on a C18 column with mobile phase: H2O (0.1%NH4HCO3)/CH3CN to afford 3-(3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepin-2-yl)-5-methyl-1,2,4-oxadiazole (Intermediate 5, 80 mg, 0.315 mmol, 92.26% yield) as white solid. LCMS calcld for C10H13ClN5O (M+H)+ m/z = 254.07, found: 254.0. [00864] Compound 87.3-[3-chloro-5-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-5-methyl-1,2,4-oxadiazole
Figure imgf000294_0001
[00865] Compound 87 was prepared similarly to that of Ex. 21 using intermediate 5. LCMS calculated for C35H42ClFN9O2 (M+H)+ m/z = 674.31; found: 674.1.1H NMR (400 MHz, CD3OD) δ 7.50 (d, J = 7.6 Hz, 1H), 7.00 – 7.27 (m, 3H), 5.21 (d, J = 55.2 Hz, 1H), 4.81 – 4.84 (m, 2H), 4.51 – 4.60 (m, 1H), 4.35 – 4.46 (m, 1H), 3.98 – 4.09 (m, 2H), 3.85 – 3.97 (m, 3H), 3.69 (d, J = 14.8 Hz, 1H), 2.90 – 3.21 (m, 6H), 2.71 – 2.79 (m, 2H), 2.66 (s, 3H), 2.35 – 2.47 (m, 1H), 1.95 – 2.27 (m, 9H), 1.72 – 1.93 (m, 5H). [00866] Intermediate 6.
Figure imgf000295_0001
[00867] Step 1. Synthesis of ethyl 3-(2-pyridyl)-1H-pyrazole-5-carboxylate (Int-6a). To a solution of 2-Ethynylpyridine (8000 mg, 77.58 mmol) in Toluene (80 mL) was added ethyl 2- diazoacetate (10622.19 mg, 93.1 mmol) and the mixture was stirred and refluxed at 110 °C for 16h. The reaction was concentrated and purified by flash column chromatography (silica gel, eluting with 27% EtOAc/PE) to afford ethyl 3-(2-pyridyl)-1H-pyrazole-5-carboxylate (9300 mg, 42.8 mmol, 55.19% yield) as a yellow solid. LCMS calculated for C11H12N3O2 (M+H)+ m/z =218.1; found:218.1. [00868] Step 2. Synthesis of ethyl 2-[3-(tert-butoxycarbonylamino)propyl]-5-(2- pyridyl)pyrazole-3-carboxylate (Int-6b). To a solution of ethyl 3-(2-pyridyl)-1H-pyrazole-5- carboxylate (6600 mg, 30.38 mmol) in DMF (70 mL) were added tert-butyl N-(3- bromopropyl)carbamate (7958.53 mg, 33.42 mmol), KI (100.88 mg, 0.61 mmol) and cesium carbonate (19749.56 mg, 60.77 mmol). The reaction was stirred at rt overnight. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated. The product ethyl 2-[3-(tert-butoxycarbonylamino)propyl]-5-(2-pyridyl)pyrazole-3-carboxylate (Int-6b, 12300 mg) was carried over without further purification. LCMS calculated for C19H27N4O4 (M+H)+ m/z =375.5; found:375.1. [00869] Step 3. Synthesis of 2-(2-pyridyl)-5,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin- 4-one (Int-6c). A mixture of ethyl 2-[3-(tert-butoxycarbonylamino)propyl]-5-(2-pyridyl)pyrazole- 3-carboxylate (Int-6b, 12.3 g, 32.85 mmol) and HCl in Dioxane (120 mL, 480 mmol) was stirred at rt for 4h. The solvent was removed followed by the addition of Methanol (110 mL) and Et3N (22.92 mL, 164.25 mmol). The reaction was stirred at 80 °C for 16h. The mixture was concentrated, and the residue was purified by flash column chromatography (silica gel, eluting with 7% MeOH/DCM) to afford 2-(2-pyridyl)-5,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-4- one (12000 mg, 52.6 mmol, 72,54% yield) as a yellow solid. LCMS calculated for C12H13N4O (M+H)+ m/z =229.3; found:229.1.1H NMR (400 MHz, CDCl3) δ 8.66 (dd, J = 4.8, 0.8 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.74 (td, J = 8.0, 2.0 Hz, 1H), 7.41 (s, 1H), 7.22-7.25 (m, 1H), 7.12 (s, 1H), 4.61 (t, J = 6.8 Hz, 2H), 3.41 (s, 2H), 2.27 – 2.38 (m, 2H). [00870] Step 4. To a solution of 2-(6-methoxy-2-pyridyl)-5,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-4-one (100 mg, 0.39 mmol) in THF (10 mL) was added LiAlH4 (132.24 mg, 3.48 mmol) at 0 °C. The reaction was stirred at 0 °C to rt overnight. The reaction was quenched with Na2SO4.10H2O. The mixture was filtered and filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, eluting with 7% MeOH/DCM) to afford 2-(6- methoxy-2-pyridyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine (70 mg, 0.287 mmol, 74.01% yield) as a yellow oil. LCMS calculated for C13H17N4O (M+H)+ m/z =245.1; found:245.1.1H NMR (400 MHz, DMSO) δ 7.68 (td, J = 8.0, 7.6 Hz, 1H), 7.44 (dd, J = 7.6, 0.8 Hz, 1H), 6.67 (dd, J = 8.4, 0.8 Hz, 1H), 6.62 (s, 1H), 4.32 – 4.39 (m, 2H), 3.89 (s, 3H), 3.82 (s, 2H), 2.99 – 3.07 (m, 2H), 1.68 – 1.78 (m, 2H), 1.40 – 1.46 (m, 1H). [00871] Compound 88. (7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-6-methyl-4-[2-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-5- yl]spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]
Figure imgf000296_0001
[00872] Compound 88 was prepared similarly to that of Ex. 21 using Intermediate 6. LCMS calculated for C37H44FN8O (M+H)+ m/z =635.4; found:635.5. 1H NMR (400 MHz, CD3OD) δ 8.52 (dd, J = 4.8, 0.8 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.82 (td, J = 7.6, 1.6 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.28 – 7.33 (m, 1H), 7.05 – 7.22 (m, 3H), 6.88 (s, 1H), 5.16 (d, J = 52.4 Hz 1H), 4.47 – 4.60 (m, 2H), 3.94 – 4.15 (m, 4H), 3.73 – 3.89 (m, 2H), 3.07 – 3.22 (m, 3H), 2.87 – 3.03 (m, 3H), 2.71 – 2.80 (m, 2H), 2.19 – 2.40 (m, 3H), 2.12 (s, 3H), 1.69 – 2.11 (m, 11H). [00873] Compound 89. (7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-4-[2-(6-methoxy-2-pyridyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-5-yl]-6- methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]
Figure imgf000297_0001
[00874] Compound 89 was prepared similarly to Compound 88. LCMS calculated for C38H46FN8O2 (M+H)+ m/z =665.4; found: 665.5.1H NMR (400 MHz, CD3OD) δ 7.66 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.45 (dd, J = 7.6, 0.4 Hz, 1H), 7.20 (td, J = 7.2, 1.2 Hz, 1H), 7.14 (td, J = 7.6, 1.2 Hz, 1H), 7.09 (dd, J = 7.6, 1.2 Hz, 1H), 6.87 (s, 1H), 6.68 (d, J = 8.4 Hz, 1H), 5.17 (d, J = 53.2 Hz, 1H), 4.43 – 4.60 (m, 2H), 3.99 – 4.15 (m, 4H), 3.96 (s, 3H), 3.78, 3.87 (d, J =14.8 Hz, 2H), 3.14 – 3.21 (m, 2H), 3.08 – 3.12 (m, 1H), 2.89 – 3.03 (m, 3H), 2.73 – 2.79 (m, 2H), 2.13 (s, 3H),1.64 – 2.50 (m, 14H). [00875] Intermediate 7.
Figure imgf000297_0002
[00876] Step 1. Synthesis of ethyl 3-chloro-5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate (Int-7a). A solution of ethyl 5-(2- nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate (Int-1c 1000 mg, 2.54 mmol) in DMF (10 mL) was added NCS (372.42 mg, 2.79 mmol) at 25 °C. Then the mixture was stirred at 80 °C for 1 h. The solution was extracted with EtOAc (10 ml), the organic phase was concentrated. The residue was purified by silica gel chromatography (eluting with EtOAc in PE from 5% to 85%). The product ethyl 3-chloro-5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate (Int-7a, 914 mg,2.131 mmol, 84.06% yield) was obtained as an oil. LCMS calculated for C16H18ClN4O6S (M+H)+ m/z =429.06, found: 429.2. [00877] Step 2. Synthesis of 3-chloro-5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Int-7b). A solution of ethyl 3-chloro-5- (2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate (Int-7a, 500 mg, 1.17 mmol) in Ethanol (5 mL) was added NH2NH2.H2O (594.85 mg, 11.66 mmol) at 25 °C. The mixture was stirred at 85 °C for 2 h. The solution was extracted with EtOAc (5 ml), the organic phase was concentrated. The residue was purified by silica gel chromatography (eluting with EtOAc in PE from 5% to 95%). The product 3-chloro-5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbohydrazide (Int-7b, 300 mg, 0.723 mmol, 62.03% yield) was obtained as a white solid. LCMS calculated for C14H16ClN6O5S (M+H)+ m/z =415.06, found: 415.0. [00878] Step 3. Synthesis of 3-chloro-2-(4,5-dimethyl-1,2,4-triazol-3-yl)-5-(2- nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine (Int-7c). To a solution of 3- chloro-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbohydrazide (Int-7b, 150 mg, 0.36 mmol) in 1,4-Dioxane (3 mL) was added 1,1,1- trimethoxyethane (65.17 mg, 0.54 mmol), Methylamine in EtOH (0.17 mL, 1.08 mmol) and a drop of AcOH (21.7 mg, 0.36 mmol) at rt. The mixture was stirred at 120 °C for 16 h in a sealed vial. The solution was extracted with EtOAc (2 ml), The water phase was concentrated. The residue was purified by silica gel chromatography (eluting with MeOH in DCM from 1% to 3%). The product 3-chloro-2-(4,5-dimethyl-1,2,4-triazol-3-yl)-5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine (95 mg, 0.210 mmol, 58.14% yield) was obtained as a white solid. LCMS calculated for C17H19ClN7O4S (M+H)+ m/z =452.09, found: 452.2. [00879] Step 4. Synthesis of 3-chloro-2-(4,5-dimethyl-1,2,4-triazol-3-yl)-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine (Intermediate 7). To a solution of 3-chloro-2-(4,5- dimethyl-1,2,4-triazol-3-yl)-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine (Int-7c, 75 mg, 0.17 mmol) in CH3CN (0.5 mL) was added 4-Methoxythiophenol (44.21 mg, 0.32 mmol) and CS2CO3 (137.07 mg, 0.42 mmol) at rt. The mixture was stirred at 25 °C for 2 h. The solution was concentrated. The residue was purified by silica gel on chromatography (eluting with MeOH in DCM from 3 % to 11%). The 3-chloro-2-(4,5-dimethyl- 1,2,4-triazol-3-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine (Intermediate 7, 40 mg, 0.15 mmol, 71.33% yield) was obtained as a white solid. LCMS calculated for C11H16ClN6 (M+H)+ m/z =267.11, found: 267.1. [00880] Compound 90. (7S)-4-[3-chloro-2-(4,5-dimethyl-1,2,4-triazol-3-yl)-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-5-yl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]
Figure imgf000299_0001
[00881] Compound 90 was prepared similarly to that of Ex. 21 using Intermediate 7. LCMS calcld for C36H45ClFN10O (M+H)+ m/z = 687.34; found: 687.4. 1H NMR (400 MHz, CD3OD) δ 7.50 (d, J = 8.0 Hz, 1H), 7.04 – 7.24 (m, 3H), 5.23 (d, J = 52.0 Hz, 1H), 4.79 – 4.96 (m, 2H), 4.42 – 4.64 (m, 2H), 3.85 – 4.15 (m, 5H), 3.77 (s, 3H), 3.70 (d, J = 14.8 Hz, 1H), 2.90 – 3.22 (m, 6H), 2.71 – 2.80 (m, 2H), 2.37 – 2.53 (m, 4H), 1.72 – 2.29 (m, 14H). [00882] Compound 91. (7S)-4-(6,8-dihydro-5H-imidazo[1,5-a]pyrazin-7-yl)-2-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-tetralin]
Figure imgf000299_0002
[00883] Compound 91 was prepared similarly to that of Ex. 21. LCMS calculated for C31H39FN7O (M+H)+ m/z = 544.31; found: 544.4. 1H NMR (400 MHz, CD3OD) δ 7.63 (s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.06 – 7.24 (m, 3H), 6.84 (s, 1H), 5.28 (d, J = 53.6 Hz, 1H), 4.77 – 4.83 (m, 2H), 4.30 – 4.40 (m, 1H), 4.05 – 4.25 (m, 4H), 3.68 – 3.78 (m, 3H), 3.15 – 3.27 (m, 3H), 2.91 – 3.09 (m, 3H), 2.71 – 2.81 (m, 2H), 2.15 – 2.31 (m, 2H), 2.05 – 2.14 (m, 4H), 1.91 – 2.04 (m, 4H), 1.74 – 1.90 (m, 3H). [00884] Example 27. Exemplary synthesis of 6-[5-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]pyridin-2-ol (Compound 92).
Figure imgf000299_0003
[00885] To a solution of (7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-4-[2-(6-methoxy-2-pyridyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-5-yl]-6- methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin] (Compound 89, 8 mg, 0.01 mmol) in THF (5 mL) was added HBr (0.5 mL, 0.01 mmol) and the reaction was stirred at 60 °C for 24h. The pH was adjusted to 8 by saturated NaHCO3 aqueous solution. Then this mixture was concentrated and purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase: H2O (0.1% NH4HCO3) / CH3CN at flow rate : 35 mL/min to afford 6-[5-[(7S)-2-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-tetralin]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]pyridin-2-ol (Compound 92, 3.25 mg,0.005 mmol, 39.05% yield) as a white solid. LCMS calculated for C37H44FN8O2 (M+H)+ m/z =651.4; found: 651.4.1H NMR (400 MHz, CD3OD) δ 7.60 (dd, J = 9.2, 7.2 Hz, 1H), 7.49 (dd, J = 7.6, 0.8 Hz, 1H), 7.17 – 7.22 (m, 1H), 7.14 (td, J = 7.6, 1.6 Hz, 1H), 7.09 (dd, J = 7.6, 0.8 Hz, 1H), 6.86 (s, 1H), 6.77 (dd, J = 7.2, 1.2 Hz, 1H), 6.46 (dd, J = 9.2, 0.8 Hz, 1H), 5.23 (d, J = 53.2 Hz, 1H), 4.46 – 4.62 (m, 3H),3.95 – 4.10 (m, 4H), 3.74, 3.83 (d, J = 14.8 Hz, 2H), 3.10 – 3.23 (m, 3H), 2.88 – 3.04 (m, 3H), 2.72 – 2.80 (m, 2H), 2.14 – 2.40 (m, 2H), 2.12 (s, 3H), 1.67 – 2.11 (m, 11H). [00886] Intermediate 8.
Figure imgf000300_0001
[00887] Step 1. Synthesis of 3-chloro-2-(2-pyridyl)-5,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-4-one (Int-8a). To a solution of 2-(2-pyridyl)-5,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-4-one (Int-6c, 2500 mg, 10.95 mmol) in DMF (23 mL) was added NCS (1755.05 mg, 13.14 mmol) at 50 °C, then the mixture was stirred at 50 °C for 16h.Then the mixture was concentrate and purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase: H2O (0.1% HCOOH) / CH3CN at flow rate : 65mL/min to afford 3-chloro-2-(2-pyridyl)-5,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-4-one (Int-8a, 2690 mg, 10.2 mmol, 93.49 %yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 4.4 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.84 (td, J = 8.0, 1.6 Hz, 1H), 7.30 – 7.38 (m, 1H), 6.46 (s, 1H), 4.60 (t, J = 7.2 Hz, 2H), 3.34 – 3.44 (m, 2H), 2.24 – 2.37 (m, 2H). LCMS calculated for C12H12ClN4O (M+H)+ m/z =263.7; found:263.2/265.2 [00888] Step 2. 3-chloro-2-(2-pyridyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine (Intermediate 8). To a solution of 3-chloro-2-(2-pyridyl)-5,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-4-one (Int-8a, 1000 mg, 3.81 mmol) in THF (100 mL) was added NaBH4 (845.1 mg, 22.84 mmol) at 0 °C. The mixture was stirred at rt for 1h, followed by the addition of Boron trifluoride diethyl etherate (4322.05 mg, 30.45 mmol). The reaction was allowed to rt and stirred overnight. Methanol was added to quenched the reaction at 0 °C and then refluxed at 45 ℃ for 16h. The mixture was concentrated and purified by flash column chromatography (silica gel, eluting with MeOH/DCM=10/1) to afford 3-chloro-2-(2-pyridyl)- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine (Intermediate 8, 710 mg, 2.85 mmol, 74.99 %yield) as a colorless oil. LCMS calculated for C12H14ClN4(M+H)+ m/z =249.7; found:249.2/251.2. [00889] Compound 93. (7S)-4-[3-chloro-2-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-5-yl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6- methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]
Figure imgf000301_0001
[00890] Compound 93 was prepared similarly to Compound 88 using Intermediate 8. LCMS calculated for C37H43ClFN8O (M+H)+ m/z = 670.3; found:669.4, 671.4. 1H NMR (400 MHz, CD3OD) δ 8.61 (d, J = 4.8 Hz, 1H), 7.85 – 7.95 (m, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.35 – 7.42 (m, 1H), 7.06 – 7.23 (m, 3H), 5.18 (d, J = 55.2 Hz, 1H), 4.77 (d, J = 28.4 Hz, 2H), 4.50 – 4.61 (m, 1H), 4.35 – 4.47 (m, 1H), 4.01 – 4.12 (m, 2H), 3.87 – 4.00 (m, 3H), 3.71 (d, J = 15.2 Hz, 1H), 2.89 – 3.25 (m, 6H), 2.76 (dd, J = 8.0, 2.8 Hz, 2H), 2.37 – 2.49 (m, 1H), 2.14 – 2.28 (m, 2H), 2.11 (s, 3H), 1.70 – 2.08 (m, 9H). [00891] Intermediate 9.
Figure imgf000301_0002
[00892] Step 1. Synthesis of methyl 3-[(2R)-2-(tert- butoxycarbonylamino)propyl]imidazole-4-carboxylate (Int-9a) To a solution of tert-butyl N- [(1R)-2-hydroxy-1-methyl-ethyl]carbamate (1.75 g, 9.99 mmol), methyl 1H-imidazole-4- carboxylate (1.51g, 11.98 mmol) and PPh3 (3705.38 mg, 16.98 mmol) in THF (100 mL) was added DIAD (3.34 mL, 16.98 mmol) dropwise at -50°C under N2. The reaction mixture was allowed to warm to rt and stirred for 16 h. The reaction mixture was concentrated under reduced pressure and then adjusted the pH to 1 by 1M HCl, extracted with EtOAc (3 x 50 mL). The aqueous layer was neutralized to pH 7-8 with sat. aq NaHCO3, and was extracted with EtOAc (3 x 70 mL). The combined organic phases were dried (Na2SO4), concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (DCM:EtOAc, 1:1) to afford methyl 3- [(2R)-2-(tert-butoxycarbonylamino)propyl]imidazole-4-carboxylate (Int-9a, 1.20 g, 4.24 mmol, 42.41 %yield) as a white solid. LCMS calculated for C13H22N3O4 (M+H)+ m/z = 284.32; found: 284.2. [00893] Step 2. Synthesis of methyl 3-[(2R)-2-aminopropyl]imidazole-4-carboxylate (Int- 9b) [00894] A solution of methyl 3-[(2R)-2-(tert-butoxycarbonylamino)propyl]imidazole-4- carboxylate (Int-9a, 1.2g, 4.24mmol) and HCl/Dioxane (6 mL, 24 mmol) in Methanol (4 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude methyl 3-[(2R)-2-aminopropyl]imidazole-4-carboxylate (Int-9b, 0.80 g) as a white solid. [00895] Step 3. Synthesis of (6R)-6-methyl-6,7-dihydro-5H-imidazo[1,5-a]pyrazin-8-one (Int-9c). A solution of methyl 3-[(2R)-2-aminopropyl]imidazole-4-carboxylate (Int-9b, 0.8 g, 4.37 mmol) and TEA (6 mL, 43.25 mmol) in Methanol (30 mL) was stirred at 50 °C overnight. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by column (DCM:MeOH) to afford (6R)-6-methyl-6,7-dihydro-5H-imidazo[1,5-a]pyrazin-8-one (Int-9c, 1.20 g, 7.94 mmol, 95.19 %yield) as a white solid. [00896] Step 4. Synthesis of (Intermediate 9). To a solution of (6R)-6-methyl-6,7-dihydro- 5H-imidazo[1,5-a]pyrazin-8-one (Int-9c, 600 mg, 3.97 mmol) in THF (30mL) was added LiAlH4 (451.88 mg, 11.91 mmol). The mixture reaction was stirred at 80 °C overnight. The reaction was quenched with Na2SO4.10H2O and dried over MgSO4. the mixture was filtered, and the filter cake was washed with THF twice. The filtrate was concentrated under reduced pressure to give not the title product(6R)-6-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (Intermediate 9, 150 mg, 1.09 mmol, 27.55 %yield) as a white solid. LCMS calculated for C7H12N3(M+H)+ m/z = 138.10; found: 138.2.1H NMR (400 MHz, CD3OD) δ 7.53 (s, 1H), 6.70 (s, 1H), 4.21 – 4.15 (m, 1H), 4.13 (d, J = 16.0 Hz, 1H), 3.93 (d, J = 15.5 Hz, 1H), 3.58 – 3.50 (m, 1H), 3.18 – 3.08 (m, 1H), 1.25 (d, J = 6.4 Hz, 3H). [00897] Compound 94. (7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-6-methyl-4-[(6R)-6-methyl-6,8-dihydro-5H-imidazo[1,5-a]pyrazin-7-yl]spiro[5,8- dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]
Figure imgf000303_0001
[00898] Compound 94 was prepared similarly to that of Ex. 21 using Intermediate 9. LCMS calculated for C32H41FN7O (M+H)+ m/z =558.3; found:558.4. 1H NMR (400 MHz, CD3OD) δ 7.66 (s, 1H), 7.51 (d, J = 6.8 Hz, 1H), 7.19 – 7.24 (m, 1H), 7.15 (td, J = 7.6, 1.6 Hz, 1H), 7.10 (dd, J = 7.6, 0.8 Hz, 1H), 6.88 (s, 1H), 5.40 (d, J = 52.8 Hz, 1H), 4.76 – 4.82 (m, 3H), 4.42 – 4.49 (m, 1H), 4.15 – 4.36 (m, 3H), 3.89 (d, J = 15.2 Hz, 1H), 3.61 – 3.75 (m, 2H), 3.50 – 3.59 (m, 1H), 3.38 – 3.47 (m, 1H), 3.14 – 3.23 (m, 1H), 2.94 – 3.12 (m, 2H), 2.74 – 2.80 (m, 2H), 2.15 – 2.51 (m, 4H), 2.13 (s, 3H), 1.93 – 2.11 (m, 4H), 1.74 – 1.88 (m, 2H), 1.27 (d, J = 6.8 Hz, 3H). [00899] Compound 95.3-chloro-N,N-dimethyl-5-[(7S)-6-methyl-2-[[1- (morpholinomethyl)cyclopropyl]methoxy]spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000303_0002
[00900] Compound 95 was prepared similarly to that of Ex. 21. LCMS calculated for C36H48ClN8O3 (M+H)+ m/z = 675.3; found: 675.1/677.1.1H NMR (400 MHz, CD3OD) δ 7.50 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H), 7.13 (td, J = 7.6, 1.2 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 4.77 (d, J = 16.8 Hz, 1H), 4.35 – 4.61 (m, 2H), 4.22 (d, J = 11.2 Hz, 1H), 4.02 – 4.15 (m, 2H), 3.81 – 3.98 (m, 2H), 3.68 (d, J = 14.4 Hz, 1H), 3.61 (t, J = 4.4 Hz, 4H), 3.09 (d, J = 10.0 Hz, 6H), 2.97 (dd, J = 38.4, 18.4 Hz, 2H), 2.70 – 2.79 (m, 2H), 2.34 – 2.52 (m, 6H), 2.30 (d, J = 12.8 Hz, 1H), 2.13 – 2.24 (m, 1H), 2.11 (s, 3H), 1.92 – 2.06 (m, 3H), 1.71 – 1.86 (m, 2H), 0.54 – 0.66 (m, 2H), 0.37 – 0.48 (m, 2H). [00901] Compound 96.3-chloro-5-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7'-hydroxy-6-methyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine- 2-carboxamide
Figure imgf000304_0001
[00902] Compound 96 was prepared similarly to that of Ex. 21. LCMS calculated for C34H43ClFN8O3 (M+H)+ m/z = 665.3; found: 665.8. 1H NMR (400 MHz, CD3OD) δ 7.11 (t, J = 8.0 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 5.28 (d, J = 54.4 Hz, 1H), 4.80 (d, J = 16.8 Hz, 2H), 4.33 – 4.53 (m, 2H), 3.95 – 4.13 (m, 3H), 3.71 – 3.91 (m, 3H), 3.05 – 3.29 (m, 10H), 2.90 – 3.04 (m, 3H), 2.75 (d, J = 18.4 Hz, 1H), 2.05 – 2.45 (m, 9H), 1.82 – 2.01 (m, 3H), 1.72 – 1.81 (m, 1H). [00903] Compound 97.3-chloro-5-[(7S)-2-[[1-[(dimethylamino)methyl]-2,2-difluoro- cyclopropyl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]- N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000304_0002
[00904] Compound 97 was prepared similarly to that of Ex. 21. LCMS calculated for C34H44ClF2N8O2 (M+H)+ m/z =669.3; found: 669.0/671.1. 1H NMR (400 MHz, CD3OD) δ 7.50 (d, J = 7.6 Hz, 1H), 7.20 (t, J = 7.2 Hz, 1H), 7.13 (td, J = 7.6, 1.2 Hz, 1H), 7.08 (d, J = 7.2 Hz, 1H), 4.87 – 4.93 (m, 1H), 4.75 – 4.82 (m, 1H), 4.47 – 4.54 (m, 1H), 4.37 – 4.46 (m, 2H), 4.23 – 4.29 (m, 1H), 4.03 – 4.13 (m, 1H), 3.84 – 3.98 (m, 2H), 3.68 (d, J = 14.8 Hz, 1H), 3.06 – 3.11 (m, 6H),2.89 – 3.06 (m, 2H), 2.63 – 2.79 (m, 3H), 2.34 – 2.51 (m, 2H), 2.21 – 2.26 (m, 6H), 2.12 – 2.20 (m, 1H), 2.10 (s, 3H), 1.93 – 2.04 (m, 2H), 1.72 – 1.87 (m, 2H), 1.51 – 1.66 (m, 1H), 1.30 – 1.40 (m, 1H). [00905] Intermediate 10. Synthesis of 2-(3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepin-2-yl)acetonitrile
Figure imgf000305_0001
[00906] Step 1. Synthesis of tert-butyl 3-chloro-2-(methylsulfonyloxymethyl)-4,5,7,8- tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate (Int-10a) [00907] To a solution of tert-butyl 3-chloro-2-(hydroxymethyl)-4,5,7,8- tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate (500 mg, 1.66 mmol) in DCM (5 mL) were added Et3N (0.35 mL, 2.49 mmol) and Methanesulfonyl Chloride (0.15 mL, 1.99 mmol) at 0 °C. The reaction was stirred at 0 °C for 2h. Then the mixture was extracted with EtOAc/H2O. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (silica gel, eluting with 5% MeOH/DCM) to afford tert-butyl 3-chloro-2-(methylsulfonyloxymethyl)-4,5,7,8-tetrahydropyrazolo[1,5- d][1,4]diazepine-6-carboxylate (Int-10a, 490 mg,0.645 mmol, 38.93% yield) as an oil. LCMS calculated for C14H23ClN3O5S (M+H)+ m/z =380.1; found:380.2/382.2. [00908] Step 2. Synthesis of tert-butyl 3-chloro-2-(cyanomethyl)-4,5,7,8- tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate (Int-10b). To a solution of tert-butyl 3- chloro-2-(methylsulfonyloxymethyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6- carboxylate (Int-10a, 490 mg, 1.29 mmol) in DMF was added NaCN (316.1 mg, 6.45 mmol) and the reaction was stirred at rt for 2h. Then the mixture was extracted with EtOAc/H2O. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase: H2O (0.1% NH4HCO3) / CH3CN at flow rate: 35 mL/min to afford tert-butyl 3-chloro-2-(cyanomethyl)- 4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate (Int-10b, 200 mg, 0.644 mmol, 49.89% yield) as a yellow oil. LCMS calculated for C14H20ClN4O2 (M+H)+ m/z =311.1; found:311.2.1H NMR (400 MHz, DMSO) δ 4.49 (s, 2H), 4.35 – 4.42 (m, 2H), 3.96 (s, 2H), 3.61 – 3.70 (m, 2H), 1.72 – 1.85 (m, 2H), 1.36 (s, 9H). [00909] Step 3. Synthesis of 2-(3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepin-2-yl)acetonitrile (Intermediate 10). A mixture of tert-butyl 3-chloro-2- (cyanomethyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (Int-9b, 100 mg, 0.32 mmol) and HCl in Dioxane (2 mL, 8 mmol) was stirred at 0 °C to rt for 2h. Then the mixture was concentrated to afford a crude product for the next step. LCMS calculated for C9H12ClN4 (M+H)+ m/z =211.1; found:211.1/213.1. [00910] Compound 98.2-[3-chloro-5-[(7S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]acetonitrile
Figure imgf000306_0001
[00911] Compound 98 was prepared similarly to that of Ex. 21 using Intermediate 10. LCMS calculated for C34H41ClFN8O (M+H)+ m/z =631.3; found:631.1/633.1.1H NMR (400 MHz, CD3OD) δ 7.49 (d, J = 7.2 Hz, 1H), 7.17 – 7.23 (m, 1H), 7.14 (td, J = 7.6, 1.2 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 5.26 (d, J = 54.8 Hz, 1H), 4.74, 4.80 (d, J = 16.4 Hz, 2H), 4.41 – 4.50 (m, 1H), 4.29 – 4.38 (m, 1H), 3.84 – 4.09 (m, 5H), 3.82 (s, 2H), 3.66 (d, J = 14.8 Hz, 1H), 3.09 – 3.28 (m, 3H), 2.89 – 3.06 (m, 3H), 2.71 – 2.81 (m, 2H), 2.12 – 2.42 (m, 4H), 2.10 (s, 3H), 1.93 – 2.08 (m, 5H), 1.74 – 1.92 (m, 3H). [00912] Intermediate 11. Synthesis of 3-chloro-2-(1-methyltetrazol-5-yl)-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4] diazepine
Figure imgf000306_0002
[00913] Step 1. Synthesis of tert-butyl 2-(1H-tetrazol-5-yl)-4,6,7,8-tetrahydropyrazolo[1,5- a] [1,4] diazepine-5-carboxylate (Int-11a). To a solution of tert-butyl 2-cyano-4,6,7,8- tetrahydropyrazolo[1,5-a] [1,4] diazepine-5-carboxylate (400 mg, 1.52 mmol), sodium azide (495.67 mg, 7.62 mmol) and Triethylamine Hydrochloride (472.28 mg, 3.43 mmol) in Toluene (10 mL). The mixture was stirred at 120 °C for 36 h. The crude product was purified by silica gel chromatography (eluted with MeOH in DCM from 1% to 10%). The crude tert-butyl 2-(1H- tetrazol-5-yl)-4,6,7,8-tetrahydropyrazolo[1,5-a] [1,4] diazepine-5-carboxylate (Int-11a, 275 mg, 0.901mmol, 59.06% yield) was obtained as yellow solid. LCMS calcld for C13H20N7O2 (M+H)+ m/z = 306.1, found: 306.1. [00914] Step 2. Synthesis of tert-butyl 2-(1-methyltetrazol-5-yl)-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (Int-11b). To a solution of tert-butyl 2- (1H-tetrazol-5-yl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (Int-11a, 100 mg, 0.33 mmol) and NaH (15.72 mg, 0.39 mmol) in DMF(0.5ml) at 0°C, followed by the addition of MeI (0.02 mL, 0.39 mmol). The reaction was stirred at 25 °C for 16 h. The crude product was purified by prep-HPLC. The product tert-butyl 2-(2-methyltetrazol-5-yl)-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (28 mg, 0.0877 mmol, 26.77 %yield) and tert-butyl 2-(1-methyltetrazol-5-yl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5- carboxylate (Int-11b, 60 mg, 0.188 mmol, 57.37 %yield) was obtained as white solid. LCMS calcld for C14H22N7O2 (M+H)+ m/z = 320.1, found:320.1. [00915] Step 3. Synthesis of tert-butyl 3-chloro-2-(1-methyltetrazol-5-yl)-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (Int-11c). To a solution of tert-butyl 2-(1- methyltetrazol-5-yl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (Int-11b, 190 mg, 0.44 mmol) in DMF (4 mL) was added NCS (70.24 mg, 0.53 mmol) at 0 °C, then the mixture was stirred at 50 °C for 16h. Then the mixture was concentrated and purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase: H2O (0.1% NH4HCO3)/MeOH at flow rate : 50 mL/min to afford tert-butyl 3-chloro-2-(1-methyltetrazol-5-yl)-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (Int-11c, 162 mg, 0.458 mmol, 77.09% yield) as a white solid. LCMS calculated for C14H21ClN7O2(M+H)+ m/z =354.1; found:354.2/356.1 [00916] Step 4. Synthesis of 3-chloro-2-(1-methyltetrazol-5-yl)-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine (Intermediate 11). To a solution of tert-butyl 3-chloro-2-(1- methyltetrazol-5-yl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (Int-11c, 50 mg, 0.14 mmol) in DCM (1.5 mL) was added HCl in dioxane (1.41 mL, 5.65 mmol) at 0 °C. The reaction was stirred at rt for 1h. Then the mixture was concentrated to afford 70 mg crude of Intermediate 11. LCMS calculated for C9H13ClN7 (M+H)+ m/z =254.7; found:254.3/256.3. [00917] Compound 99. (7S)-4-[3-chloro-2-(1-methyltetrazol-5-yl)-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-5-yl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-methyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]
Figure imgf000307_0001
[00918] Compound 99 was prepared similarly to that of Ex. 21 using Intermediate 11. LCMS calculated for C34H42ClFN11O (M+H)+ m/z = 674.3; found: 674.5.1H NMR (400 MHz, CD3OD) δ 7.50 (d, J = 7.6 Hz, 1H), 7.20 (td, J = 7.2, 1.6 Hz, 1H), 7.14 (td, J = 7.6, 1.6 Hz, 1H), 7.09 (d, J = 6.8 Hz, 1H), 5.23 (d, J = 53.2 Hz, 1H), 4.60 – 4.66 (m, 2H), 4.41 – 4.54 (m, 1H), 4.33 (s, 3H), 4.02 – 4.11 (m, 2H), 3.89 – 3.98 (m, 3H), 3.71 (d, J = 14.8 Hz, 1H), 3.10 – 3.20 (m, 2H), 3.00 – 3.10 (m, 2H), 2.90 – 2.99 (m, 2H), 2.76 (d, J = 5.2 Hz, 2H), 2.36 – 2.51 (m, 1H), 2.14 – 2.31 (m, 3H), 2.11 (s, 3H), 1.77 – 2.06 (m, 9H). [00919] Example 28. Exemplary synthesis of 3-chloro-5-[(7S)-6-ethyl-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrido[4,3-d]pyrimidine- 7,1'-tetralin]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 100).
Figure imgf000308_0001
[00920] Step 1. Synthesis of (7S)-6-ethylspiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-2,4-diol (100b). To a solution of (7S)-spiro[6,8-dihydro-5H-pyrido[4,3-d]pyrimidine- 7,1'-tetralin]-2,4-diol (100a prepared similarly to that of 64h, 400 mg, 1.41 mmol) in Ethanol (6.7 mL) was added acetaldehyde (0.8 mL, 14.12 mmol) and NaBH3CN (266.15 mg, 4.24 mmol). The mixture was stirred at 30 °C for 2 days. NaBH3CN (266.15 mg, 4.24 mmol) and acetaldehyde (0.8 mL, 14.12 mmol) were added, and the reaction was continued to stir at 30 °C for 6 h. The reaction mixture was quenched with water and filtered, dry over in vacuum to afford (7S)-6-ethylspiro[5,8- dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-2,4-diol (100b, 430 mg, 0.884 mmol, 62.60 %yield) as yellow solid. LCMS calculated for C18H22N3O2 (M+H)+ m/z = 312.17; found: 312.0. [00921] Step 2. Synthesis of (7S)-2,4-dichloro-6-ethyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-tetralin] (100c). A solution of (7S)-6-ethylspiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1’-tetralin]-2,4-diol (100b, 430 mg, 0.88 mmol) in POCl3 (4065.43 mg, 26.51 mmol) was stirred at 100 °C for 5 h. The reaction mixture was concentrated, diluted with DCM and DIEA, extracted with DCM, dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 10% EtOAc/PE) to afford (7S)-2,4-dichloro-6- ethyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin (100c, 120 mg, 0.345 mmol, 38.99% yield) as a yellow solid. LCMS calculated for C18H20Cl2N3 (M+H)+ m/z = 348.10, 350.10; found: 348.1, 350.1. [00922] Step 3. Synthesis of 3-chloro-5-[(7S)-2-chloro-6-ethyl-spiro[5,8- dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (100d). A solution of (7S)-2,4-dichloro- 6-ethyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin] (100c, 120mg, 0.34mmol), 3- chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (83.63 mg, 0.34 mmol) and DIEA (133.59 mg, 1.03 mmol) in DMSO (1.2 mL) was stirred at 30 °C for 16 h. The reaction mixture was filtered, the filtrate was purified by prep-HPLC (0.1% NH4HCO3), to afford 3-chloro-5-[(7S)-2-chloro-6-ethyl-spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (100d, 110 mg, 0.198 mmol, 57.57 %yield) as a white solid. LCMS calculated for C28H34Cl2N7O (M+H)+ m/z = 554.22, 556.22; found: 554.0, 556.0. 1H NMR (400 MHz, DMSO) δ = 7.47 (d, J=7.5 Hz, 1H), 7.19 (t, J=6.9 Hz, 1H), 7.13 (t, J=6.8, 1H), 7.07 (d, J=6.9, 1H), 4.85 – 4.71 (m, 2H), 4.51 – 4.38 (m, 2H), 4.02 – 3.86 (m, 2H), 3.74 (dd, J=45.1, 15.6 Hz, 2H), 3.02 – 2.91 (m, 7H), 2.82 (d, J=18.3 Hz, 1H), 2.82 (d, J=18.3 Hz, 1H), 2.76 – 2.62 (m, 2H), 2.37 – 1.99 (m, 4H), 1.94 – 1.64 (m, 4H), 0.84 (t, J=7.0 Hz, 3H). [00923] Step 4. Synthesis of 3-chloro-5-[(7S)-6-ethyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-tetralin]-4-yl]- N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 100) [00924] The mixture of 3-chloro-5-[(7S)-2-chloro-6-ethyl-spiro[5,8-dihydropyrido[4,3- d]pyrimidine-7,1'-tetralin]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine- 2-carboxamide (100d, 30 mg, 0.05 mmol), [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (43.07 mg, 0.27 mmol) and Sodium Tert-Butoxide (7.8 mg, 0.08 mmol) in DMSO (1 mL) was stirred at 20°C for 3h until the reaction mixture is clear. The reaction mixture was purified by prep-HPLC (0.1% NH4HCO3) to afford 3-chloro-5-[(7S)-6-ethyl-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 100, 16 mg, 0.0237 mmol, 43.88 %yield) as a white solid. LCMS calculated for C36H46ClFN8O2 (M+H)+ m/z = 677.35; found: 677.0.1H NMR (400 MHz, CD3OD) δ = 7.52 (d, J=7.7 Hz, 1H), 7.17 (dd, J=10.7, 4.3 Hz, 1H), 7.12 (td, J=7.3, 1.3 Hz, 1H), 7.07 (d, J=6.5 Hz, 1H), 5.26 (d, J=53.8 Hz, 1H), 4.93 – 4.86 (m, 1H), 4.76 (dd, J=16.7, 6.5 Hz, 1H), 4.56 – 4.34 (m, 2H), 4.16 – 3.72 (m, 6H), 3.16 (m, 3H), 3.10 (d, J=2.1 Hz, 3H), 3.08 (s, 3H), 3.06 – 2.86 (m, 3H), 2.75 (d, J=7.0 Hz, 2H), 2.53 – 1.71 (m, 14H), 0.95 (t, J=7.0 Hz, 3H). [00925] Example 29. Exemplary synthesis of 3-chloro-5-[(7S)-6-ethyl-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrido[4,3-d]pyrimidine- 7,1'-tetralin]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 101).
Figure imgf000310_0001
[00926] Step 1. Synthesis of (7S)-2,4-dichloro-7'-fluoro-spiro[6,8-dihydro-5H-pyrido[4,3- d]pyrimidine-7,1'-indane] (101b) [00927] The mixture of (7S)-7'-fluorospiro[6,8-dihydro-5H-pyrido[4,3-d]pyrimidine-7,1'- indane]-2,4-diol (100a, 1.2 g, 4.18 mmol) in POCl3 (12.59 mL, 137.49 mmol) was added DIEA (1.46 mL, 8.35 mmol) and heated at 100 °C for 5 h. The reaction was cooled down to rt, concentrated and dissolved in DCM (20 mL) at 0 ℃. The mixture was added DIEA(1.5 mL) and was stirred at 0℃ for 2h, followed by the addition of NH4HCO3 (aq, 20mL). The organic layer was dried over Na2SO4 and concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 100% EtOAc/PE) to afford (7S)-2,4-dichloro-7'-fluoro-spiro[6,8-dihydro-5H- pyrido[4,3-d]pyrimidine-7,1'-indane] (101b, 1.14 g, 3.52 mmol, 84.19 %yield as brown solid. LCMS calculated for C15H13Cl2FN3 (M+H)+ m/z = 324.1, 326.1; found: 324.1, 326.1. [00928] Step 2. Synthesis of 3-chloro-5-[(7S)-2-chloro-7'-fluoro-spiro[6,8-dihydro-5H- pyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide (101c). The mixture of (7S)-2,4-dichloro-7'-fluoro-spiro[6,8- dihydro-5H-pyrido[4,3-d]pyrimidine-7,1'-indane] (101b, 300 mg, 0.93 mmol), 3-chloro-N,N- dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Int-, 224.61 mg, 0.93 mmol) and DIEA (0.64 mL, 3.7 mmol) in DMSO (2 mL) was stirred at 20 °C for 30 h. The reaction mixture was purified by prep-HPLC on a C18 column (20-35 uM, 100 A, 40 g) with mobile phase: H2O ( 0.1%NH4HCO3)/MeCN at flowrate: 50 mL/min to give 3-chloro-5-[(7S)-2- chloro-7'-fluoro-spiro[6,8-dihydro-5H-pyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (364 mg, 0.686 mmol, 74.16% yield). LCMS calculated for C25H27Cl2FN7O (M+H)+ m/z = 530.2/532.2; found: 530.1/532.2 [00929] Step 3. Synthesis of 3-chloro-5-[(7S)-2-chloro-6-(cyanomethyl)-7'-fluoro- spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (101d). To a solution of 3-chloro-5- [(7S)-2-chloro-7'-fluoro-spiro[6,8-dihydro-5H-pyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N- dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (101c, 364 mg, 0.69 mmol) in DMF (2mL) was added Cesium carbonate (670.78 mg, 2.06 mmol) and bromoacetonitrile (0.1 mL, 1.37 mmol). The reaction was heated at 50 °C overnight. The reaction mixture was purified by prep-HPLC on a C18 column (20-35 uM, 100 A, 40 g) with mobile phase:H2O ( 0.1%NH4HCO3)/MeCN to give 3-chloro-5-[(7S)-2-chloro-6-(cyanomethyl)-7'-fluoro- spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (370 mg, 0.650 mmol, 94.68% yield). LCMS calculated for C27H28Cl2FN8O (M+H)+ m/z = 569.17; found: 569.2 [00930] Step 4. Synthesis of 3-chloro-5-[(7S)-6-(cyanomethyl)-7'-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrido[4,3-d]pyrimidine- 7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 101). The mixture of 3-chloro-5-[(7S)-2-chloro-6-(cyanomethyl)-7'-fluoro- spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (101d, 30 mg, 0.05 mmol), [(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (41.93 mg, 0.26 mmol) and sodium tert- butoxide (7.59 mg, 0.08 mmol) in DMSO (1 mL) was stirred at 20 °C under Argon for 2 h. The reaction mixture was purified by prep-HPLCH2O ( 0.1%NH4HCO3)/MeCN to afford 3-chloro-5- [(7S)-6-(cyanomethyl)-7'-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'-indane]-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 101, 10 mg, 0.0135 mmol, 25.60 %yield) as a white solid. LCMS calculated for C35H41ClF2N9O2 (M+H)+ m/z = 692.3; found: 692.3.1H NMR (400 MHz, CD3OD) δ 7.34 – 7.39 (m, 1H), 7.12 – 7.14 (m, 1H), 6.95 – 7.00 (m, 1H), 5.26 (d, J=53.8, 1H), 4.82, 4.88 (d, J = 16.8 Hz, 2H), 4.39 – 4.53 (m, 2H), 3.87 – 4.16 (m, 6H), 3.56, 3.73 (d, J = 17.6 Hz, 2H), 3.12 – 3.25 (m, 4H), 3.10 (s, 3H), 3.08 (s, 3H), 2.96 – 3.04 (m, 2H), 2.80 (d, J=17.6, 1H), 2.57 – 2.65 (m, 1H), 1.83 –2.44 (m, 10H). [00931] Compound 102. 3-chloro-5-[(7S)-6-(cyanomethyl)-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- tetralin]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide
Figure imgf000312_0001
[00932] Compound 102 was prepared similarly to that of Ex. 28. LCMS calculated for C36H44ClFN9O2 (M+H)+ m/z = 688.33, 690.33; found: 689.5, 691.6.1H NMR (400 MHz, CD3OD) δ = 7.50 (d,J=7.8, 1H), 7.26 (dd,J=10.6, 4.4, 1H), 7.20 (td,J=7.4, 1.4, 1H), 7.15 (d,J=7.4, 1H), 5.27 (d,J=54.4, 1H), 4.91 (d,J=16.6, 1H), 4.80 (d,J=16.6, 1H), 4.36 – 4.56 (m, 2H), 4.04 – 4.22 (m, 3H), 3.86 – 4.03 (m, 3H), 3.45 (m,J= 17.2, 2H), 3.12 – 3.26 (m, 3H), 3.10 (s, 3H), 3.07 (s, 3H), 2.92 – 3.06 (m, 3H), 2.73 – 2.83 (m, 2H), 2.33 – 2.47 (m, 1H), 1.73 – 2.33 (m, 11H). [00933] Compound 103. 3-chloro-5-[(7S)-6-ethyl-7'-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[5,8-dihydropyrido[4,3-d]pyrimidine-7,1'- indane]-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide.
Figure imgf000312_0002
[00934] Compound 103 was prepared similarly to that of Ex. 28. LCMS calculated for C35H44ClF2N8O2 (M+H)+ m/z = 681.32; found: 681.3, 683.3. 1H NMR (400 MHz, CD3OD) δ = 7.26– 7.31 (m, 1H),7.04 –7.08 (m, 1H),6.89 – 6.93 (m, 1H), 5.26 (d,J=53.8, 1H), 4.73 – 4.82 (m, 2H), 4.36 – 4.52 (m, 2H), 3.66 – 4.14 (m, 6H), 3.14 – 3.25 (m, 3H), 3.10 (s, 3H),3.08 (s, 3H), 2.91 –3.04 (m, 3H), 2.80 (d,J=17.6, 1H), 2.55 –2.65 (m, 1H),1.81–2.46 (m, 12H), 1.07 (t,J=7.2, 3H). [00935] Example 30: Nucleotide Exchange Assay: [00936] Ras proteins cycle between an active, GTP bound state, and an inactive GDP- bound state. This activity is tightly regulated by GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). GEFs, such as SOS1/2, activate Ras proteins by exchanging GDP for GTP, thus returning Ras to its active conformation (Simanshu, Nissley, & McCormick, 2017). Therefore, a small molecule that binds K-Ras in a manner that prevents SOS-mediated nucleotide exchange locks KRas in its inactive state. Homogenous time resolved fluorescence (HTRF) was used to detect SOS-mediated binding of a fluorescent GTP analog, GTP-DY-647P1 (Jena Biosciences NU-820-647P1) to GST-tagged KRASG12D (2-169, Reaction Biology, MSC- 11-539). [00937] GST-tagged KRASG12D (2-169) and anti-GST MAb Tb Cryptate Gold (CisBio 61GSTTLB) were diluted into assay buffer (20 mM HEPES, pH 7.3, 150 mM NaCl, 5 mM MgCl2, 0.05% BSA 0.0025% NP40, 1 mM DTT) to prepare a 2.5X donor solution.5X compound was added to the protein mixture and incubated for 1 h at RT.2.5X acceptor solution containing SOS1cat (564-1049, Reaction Biology MSC-11-502) and GTP-DY-647P1 were then added to the donor KRAS mixture such that the final concentration of the reaction contained 5 nM GST-tagged KRASG12D (2-169), 20 nM SOScat, and 150 nM GTP. The reaction was monitored using at RT with the Envision multimode plate reader (Ex/Em 337/665, 620 nM) up to 90 minutes at 5 minute intervals. Data was blanked to reactions without SOS1 and % inhibition was calculated such that DMSO only = 0% and blank = 100%. Curve fitting was done using a 4 parameter fit. NEA KRAS G12D IC50 (uM) values of selected compounds are depicted in Table 2 with compounds having a value <0.01 uM as ++++; > 0.01 uM to 0.1 uM as +++; > 0.1 uM to 1 uM as ++; > 1 uM to 20 uM as +; and >20 uM as NA. [00938] Example 31: Protein Constructs for Protein-Protein Interaction: Table 1: Assay, Protein construct, and protein construct sequences
Figure imgf000314_0001
[00939] Example 32. Recombinant Protein Production: [00940] Biotinylated KRAS wt and KRAS G12D/V proteins were expressed and purified in conditions similar to those previously reported (Tran, et al., 2021) (Zhang, et al., 2020). Briefly, KRAS (1-169) proteins were expressed in E. coli at 18°C with an upstream TEV cleavage site (ENLFYQS) followed an Avi tag sequence (GLNDIFEAQKIEWHE). KRAS expression constructs contained both a His6 and maltose-binding protein (MBP) tags at the N-terminus for Ni-NTA column purification prior to overnight TEV cleavage and MBP column purification. The avi-tagged NRAS expression construct contained both a His6 tag and SUMO cleavage sige at the N-terminus for Ni-NTA column purification followed by His-ULP1 digestion overnight. All avi- tagged RAS proteins were dialyzed into buffer containing ATP, biotin, and BirA followed by purification over a second Ni-NTA column and then run over a size exclusion HiLoadTM 26/600 SuperdexTM column in 20 mM HEPES, pH 7.5, 300 mM NaCl, 5 mM MgCl2, and 1 mM TCEP. Fractions containing the protein of interest were pooled, concentrated, and confirmed by intact mass spectrometry. To prepare ‘GTP’ loaded KRAS and NRAS, biotinylated KRAS or NRAS was nucleotide exchanged from GDP-bound protein to GppNHp-bound (Jena Biosciences, NU-401- 50) protein in the presence of alkaline phosphatase and excess GppNHp as previously described and the resulting nucleotide content was confirmed by HPLC reverse phase analytical chromatography (Donohue, et al., 2019) (Tran, et al., 2021). [00941] His-tagged RAF1 (52-131) was similarly expressed in E. coli at 18°C overnight with an upstream TEV cleavage site. His-tagged RAF1 expression construct contained both a His6 and MBP tags at the N-terminus for Ni-NTA column purification followed by MBP-tagged TEV digestion overnight. RAF1 protein samples were further purified over a MBP column followed by a Ni-NTA column and a second MBP column. The fractions containing the protein of interest were pooled, concentrated, and further purified over a HiLoadTM 16/600 SuperdexTM 75 pg size exclusion column into 20mM HEPES, pH8.0, 200mM NaCl, 5mM TCEP. [00942] Example 33: Protein-Protein Interaction (PPI) Assay: [00943] When RAS proteins are in the active GTP-bound conformation, they bind the effector protein RAF1 at the N-terminus Ras-binding domain (RBD, residues 52-131) (Tran, et al., 2021). Homogenous time resolved fluorescence (HTRF) was used to monitor the interaction between wt or mutant KRAS and RAF1 or wt NRAS and RAF1. Compounds were assayed in the presence of KRAS G12D/V and RAF1 versus wt KRAS to assess activity against mutant and w.t. KRAS. Similarly, compounds were then assayed in the presence of w.t. NRAS and RAF1 to assess RAS isoform selectivity. In all assay formats, His-tagged RAF1 protein was incubated with the HTRF donor, anti-6His Tb Cryptate gold (Cisbio 61DB10RDF), and biotinylated RAS proteins were incubated with the HTRF acceptor, streptavidin-d2 (CisBio 610SADLA). The intensity of the fluorescence signal emitted is proportional to binding between the two proteins. The donor solution was prepared by mixing 16 nM His-tagged RAF1 in protein dilution buffer with 1:100 anti-6His Tb cryptate in PPI-Terbium detection buffer. 16 nM biotinylated RAS protein was diluted into protein dilution buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.1 mM MgCl2, 1 mM TCEP, 0.005% Tween20) and mixed with 1:2000 Streptavidin-d2 diluted in PPI-Terbium detection buffer (CisBio 61DB10RDF).50X compound in DMSO was mixed with 16 nM KRAS- acceptor solution and incubated for 30 minutes at room temperature. After compound pre- incubation with KRAS, the RAF1 donor solution was added to the KRAS-acceptor solution and incubated for 1 hour at room temperature. The fluorescence signal emitted was monitored at 665 nm and 615 nm using an Envision multimode plate reader. The HTRF ratio (665/615) was calculated and normalized to 0% inhibition in the absence of compound and 100% inhibition in the presence of untagged RAF1 protein. PPI KRAS G12D/RAF1, KRAS G12V/RAF1, w.t.KRAS/RAF1 and NRAS/RAF1 IC50 (uM) values of selected compounds are depicted in Table 2 and Table 3 with compounds having a value <0.1 uM as ++++; > 0.1 uM to 1 uM as +++; > 1 uM to 10 uM as ++; > 10 uM to 100 uM as +; and >100 uM as NA. [00944] Compounds described herein are active against KRAS G12 mutant and other alleles representative by PPI-G12D, PPI-G12V and PPI-w.t.KRAS potency for broad activity against mutant KRAS and wtKRAS amplification driven malignancies. [00945] Example 34. pERK Inhibition cellular HTRF assay in AGS Cell Lines (Method A) [00946] The Phospho-ERK cellular HTRF assay measures ERK protein phosphorylated at Thr202/Tyr204 as a readout of MAPK pathway activation (Cisbio 64ERKPEH). AGS cells (ATCC CRL-1739) are cultured in the complete medium containing 10% fetal bovine serum and 1x Penicillin/Streptomycin at 37oC in a humid atmosphere of 5% CO2 in the air (AGS cells: RPMI 1640 medium). [00947] On day 1, the cells are plated in tissue-culture treated 96-well plates at the specified densities and allowed to attach for overnight (AGS: 30,000 cells/well). On day 2, the cells are treated with the serially diluted compound solutions in a final concentration of 0.5 % DMSO. After the treatment for the specified time (AGS cells: 3 hours), the supernatant is removed, and the cells are lysed by the lysis buffer supplied with the kit. Then, the cell lysates are treated with the detection reagents overnight at 4oC in darkness. On day 3, the fluorescence intensities at the wavelengths 665 and 620 nm are measured by the Envision plate reader (Perkin Elmer). The data are processed and fitted to a 4-parameter logistic model for IC50 calculations (GraphPad Prism 9). [00948] Example 35. pERK In Cell Western (ICW) assay (Method B) [00949] pERK ICW is a high throughput screening assay to evaluate the cellular potency of mutant KRAS small molecule inhibitors. KRAS mutant cell line AGS (KRASG12D) wer purchased from ATCC and maintained in DMEM and RPMI medium supplemented with 10% fetal bovine serum and Penicillin/Streptomycin. [00950] Cells grown in exponential phase were trypsinized, resuspended in fresh media, and viable cells were counted using a cell counter with Trypan Blue (BioRad TC20). Cells were seeded into 384-well plate (Greiner 781091) at density of 5,000 cells/well for AGS and allowed to grow overnight in a 37˚C CO2 incubator. The next day, compounds were dispensed into wells with a ½ log, 10-point serial dilution and top concentration of 10 µM using Tecan D300e dispenser and incubated for 3 hours in a 37 ˚C CO2 incubator. Cells were then fixed with paraformaldehyde (Electron Microscopy Sciences, 15710, 4% final concentration) for 30 min, permeabilized with wash buffer (1X PBS + 0.1% Triton X-100) for 30 min and blocked with Odyssey blocking buffer (Li-COR 927-70001) for 1 hour, all at room temperature (RT). Phospho-ERK antibody (CST 4370L) was diluted 1:500 in Odyssey blocking + 0.2% Tween 20 and incubated with cells overnight at 4 ˚C. The next day, plates were washed 5x with wash buffer, incubated with IRDye 800 CW, Goat anti-Rabbit secondary antibody (Li-COR 926-32211, 1:500) and DRAQ5 (CST 4084L, 1:5,000) diluted in in Odyssey blocking + 0.2% Tween 20 for 1 hour, washed 5x, and imaged on an Odyssey CLx imaging system. [00951] For data analysis, signal intensities from 800 (phosphor-ERK) and 700 (DRAQ5) channels were extracted, and phospho-ERK signals were normalized to DRAQ5 signals for each well and percent of DMSO control values were computed. Data were then imported into Graphpad Prism to compute half-maximal inhibitory concentrations (IC50) using a 4-parameter variable slope model. Z-factor for each plate was computed from signals derived from wells treated with either DMSO or 5 µM of Trametinib. AGS pERK ICW (Method B) IC50 (uM) values of selected compounds are depicted in Table 2 with compounds having a value 0.001 uM to 0.01 uM as ++++; > 0.01 uM to 0.1 uM as +++; > 0.1 uM to 1 uM as ++; 1 uM to 10 uM as + and > 10 uM as NA. [00952] Table 2 includes NEA KRAS G12D IC50 (uM) values (<0.01 uM as ++++; > 0.01 uM to 0.1 uM as +++; > 0.1 uM to 1 uM as ++; > 1 uM to 20 uM as +; and >20 uM as NA), PPI KRAS G12D/RAF1 IC50 (uM) values (<0.1 uM as ++++; > 0.1 uM to 1 uM as +++; > 1 uM to 10 uM as ++; > 10 uM to 100 uM as +; and >100 uM as NA), AGS pERK HTRF (Method A) IC50 (uM) values (<0.01 uM as ++++; > 0.01 uM to 0.1 uM as +++; 0.1 uM to 1 uM as ++; 1 uM to 20 uM as + and >20 uM as NA), and AGS pERK ICW (Method B) IC50 (uM) values (0.001 uM to 0.01 uM as ++++; > 0.01 uM to 0.1 uM as +++; > 0.1 uM to 1 uM as ++; 1 uM to 10 uM as + and > 10 uM as NA) of selected compounds. ND indicates not determined. Table 2: IC50 (uM) values for various assays
Figure imgf000317_0001
Figure imgf000318_0001
Figure imgf000319_0001
Figure imgf000320_0001
Table 3 includes KRASG12V/RAF1, wtKRAS/RAF1 and wtNRAS/RAF1 PPI IC50 (uM) values of selected compounds; with compounds having a value <0.1 uM as ++++; 0.1 uM to 1 uM as +++; >1 uM to 10 uM as ++; >10 uM to 100 uM as +; and >100 uM as NA. Table 3: IC50 (uM) values for KRASG12V/RAF1, wtKRAS/RAF1 and wtNRAS/RAF1 PPI
Figure imgf000320_0002
[00953] Example 36. Quantification of cytokine/chemokine release under treatment in HPAC cells with a KRAS inhibitor [00954] Previous studies have shown KRAS-mutation-mediated MAPK signaling activation in tumor cells leads to immunosuppressive tumor microenvironment partially by increasing tumor cell immunosuppressive cytokine (e.g. GM-CSF) while reducing immunostimulatory chemokine (e.g. CXCL10 and CCL20) release (reference article, Huang et al., 2021, KRAS mutation: from undruggable to druggable in cancer). This assay aims to determine whether mutant KRAS inhibitor treatment can reverse tumor cell cytokine/chemokine release by inhibiting KRAS/MAPK signaling. [00955] Cytokine/chemokine levels in tumor cell-conditioned medium can be measured by ELISA (Enzyme-Linked Immunosorbent Assay) kit. Endpoint relative cell numbers are also measured by CTG (CellTiter-Glo) assay as cytokine/chemokine release is directly affected by the number of assayed tumor cells. [00956] KRAS mutant cell line HPAC (KRASG12D) was purchased from ATCC (ATCC CRL-2119) and maintained in DMEM medium supplemented with 10% fetal bovine serum and Penicillin/Streptomycin (complete DMEM medium, thereafter). [00957] HPAC cells grown in exponential phase were trypsinized, resuspended in fresh media, and viable cells were counted using a cell counter with Trypan Blue (BioRad TC20). Cells were seeded into 6-well plate (Corning 3506) at density of 0.75 million cells/well in 1.5 mL complete DMEM medium and allowed to grow overnight in a 37˚C CO2 incubator. The next day, the medium was replaced by the same volume of fresh complete DMEM medium with 500 nM of each compound (e.g., compound 53, 61, 63, 64, 65, 69, or 96) or DMSO control, triplet samples for each compound treatment or control. The cells were then cultured for another 48 hours in 37˚C CO2 incubator. [00958] By the end of drug treatment, 1 mL of supernatant from 1.2 mL conditioned medium of each sample after centrifugation (6000 rpm) was collected and analyzed by R&D Systems’ GM-CSF (R&D DGM00RD), CXCL10 (R&D DIP100), and CCL20 (R&D DM3A00) standard curve-based ELISA kits following the manufacturers’ protocols. Fresh complete DMEM, not conditioned, was used as BLK control of the assay. [00959] To determine relative cell numbers by the end of assay, cells were initially seeded in a 384-well plate in 40 µL complete DMEM medium at the same density (0.5 million cells/mL), treated with the same concentration of a compound (e.g., compound 53, 61, 63, 64, 65, 69, or 96) or control, and incubated the same time courses in parallel in 6-well plates. Relative cell numbers were assayed by dispensing 40 µL of CellTiter-Glo (Promega G7573) reagent for luminance reading following manufacturers’ protocol. [00960] For data analysis, corrected ELISA OD reading (OD450 subtracts OD570 of each sample) was used to determine cytokine/chemokine level using the formula generated from a standard curve of each ELISA assay. The cytokine/chemokine level was normalized by relative cell number determined by CTG assay of each sample. [00961] FIG.1 shows levels of immunosuppressive cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) (left chart) and immunostimulatory chemokines C-X-C motif chemokine ligand 10 (CXCL10) (middle chart) and Chemokine (C-C motif) ligand 20 (CCL20) (right chart) in KRAS G12D mutant HPAC cell conditioned medium were measured by each cytokine/chemokine specific Enzyme-Linked-Immunosorbent-Assay (ELISA), and normalized by tumor cell numbers of each sample. * p <0.05, ** p <0.01, *** p<0.001, **** p <0.0001. [00962] As shown in FIG.1, exemplified by compounds 53, 61, 63, 64, 65, 69 and 96, compounds described herein may reprogram the tumor microenvironment (TME) in favor of antitumor immunity, by modulating tumor cell cytokine/chemokine release. Specifically, compound treatment reduces immunosuppressive cytokine release while increasing immunostimulatory chemokine release in KRAS mutant cells (refer to histograms in FIG.1). These data support clinical studies combining compounds described herein (e.g., Formula (II), Formula (II*), etc.) with existing checkpoint inhibitors (inhibitors targeting: cytotoxic T lymphocyte associated antigen 4 (CTLA-4), e.g. Yervoy/lpilimumab; programmed death 1/programmed death-ligand 1 (PD-1/PD-L1), e.g. Keytruda/pembrolizumab; and lymphocyte- activation gene 3 (LAG-3), e.g. BMS-986016/relatlimab) for various types of cancers harboring oncogenic KRAS. [00963] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS WHAT IS CLAIMED IS: 1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor and a compound of Formula (II):
Figure imgf000323_0001
Formula (II) or a pharmaceutically acceptable salt thereof wherein: M is selected from O, S, SO, SO2, and NR3; R1 is selected from C3-C12 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl-SO2R20, C1- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; Y is selected from a bond, O, S and NR5; R2 is selected from -L-N(R21)2, -L-OR21, heterocycle, C1-C6 alkyl, -L-heterocycle, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R21)2, -L-C1-C6 haloalkyl, -L- OR21, -L-NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L- N(R21)C(O)(OR21), -L-OC(O)N(R21)2, and -LC(=O)OC1-C6 alkyl, wherein the heterocycle, the aryl portion of -L-NR21C(O)-aryl, the heterocycle portion of -L-heterocycle, the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of the -L- aryl and the heteroaryl portion of the -L-heteroaryl are each optionally substituted with one or more R7, and wherein when Y is a bond, O, or S, R2 is further selected from hydrogen; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkoxyalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; n is selected from 0 to 2; each R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, hydroxyl, halogen, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; each R5 is independently selected from hydrogen or C1-C6 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; each R7 is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R5)2; each R20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, =NH, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R21 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; and B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, C1-6 alkyl-N(R20)2, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. 2. The method of claim 1, wherein the immunomodulator inhibitor is a PD-1 inhibitor. 3. The method of claim 2, wherein the PD-1 inhibitor is an antibody or antigen-binding fragment. 4. The method of claim 2, wherein the PD-1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, and a biosimilar thereof. 5. The method of claim 2, wherein the PD-1 inhibitor is nivolumab or a biosimilar thereof.
6. The method of claims 4 or 5, wherein the therapeutically effective amount of nivolumab or biosimilar thereof in the combination is about 240 mg administered every two weeks. 7. The method of claims 4 or 5, wherein the therapeutically effective amount of nivolumab, or biosimilar thereof, in the combination is about 480 mg administered every four weeks. 8. The method of claim 4, wherein the PD-1 inhibitor is pembrolizumab or a biosimilar thereof. 9. The method of claim 4, wherein the therapeutically effective amount of pembrolizumab or biosimilar thereof in the combination is about 200 mg administered every three weeks. 10. The method of claim 4, wherein the wherein the PD-1 inhibitor is cemiplimab or a biosimilar thereof. 11. The method of claim 1, wherein the immunomodulator inhibitor is a PD-L1 inhibitor. 12. The method of claim 11, wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, and a biosimilar thereof. 13. The method of claim 12, wherein the PD-L1 inhibitor is atezolizumab or a biosimilar thereof. 14. The method of claim 1, wherein the immunomodulator inhibitor is a CTLA-4 inhibitor. 15. The method of any one of claims 1 to 14, wherein the immunomodulator inhibitor is administered orally. 16. The method of any one of claims 1 to 15, wherein the cancer is selected from: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. 17. The method of any one of claims 1 to 16, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer. 18. The method of any one of claims 1 to 16, wherein the cancer is non-small cell lung cancer. 19. The method of any one of claims 1 to 16, wherein the cancer is small cell lung cancer. 20. The method of any one of claims 1 to 16, wherein the cancer is colorectal cancer.
21. The method of any one of claims 1 to 16, wherein the cancer is rectal cancer. 22. The method of any one of claims 1 to 16, wherein the cancer is pancreatic cancer. 23. The method of any one of claims 1 to 16, wherein the cancer is a solid tumor cancer. 24. The method of any one of claims 1 to 16, wherein the cancer is selected from a KRas mutant-associated cancer. 25. The method of any one of claims 1 to 16, wherein the cancer is selected from a KRas wildtype-associated cancer. 26. The method of any one of claims 1 to 16, wherein the cancer is selected from a KRas G12D-associated cancer, a KRas G12V-associated cancer, and a KRas wildtype-associated cancer. 27. The method of any one of claims 1 to 16, wherein the cancer is a KRas G12D-associated cancer. 28. The method of any one of claims 1 to 16, wherein the cancer is a KRas G12V-associated cancer. 29. The method of any one of claims 25 to 26, wherein the KRas wildtype is hyperactivated. 30. The method of any one of claims 1 to 29, wherein the immunomodulator inhibitor synergistically increases the sensitivity of cancer cells to the compound or salt of Formula (II). 31. The method of claim 1, wherein the combination exhibits synergy. 32. The method of any one of claims 1 to 31, wherein the therapeutically effective amount of the combination of the immunomodulator inhibitor and the compound or salt of Formula (II) results in an increased duration of overall survival, an increased duration of progression free survival, an increase in tumor growth regression, an increase in tumor growth inhibition, an increased duration of stable disease in the subjects relative to treatment with only the compound or salt of Formula (II), or any combination thereof. 33. The method of any one of claims 1 to 32, wherein the therapeutically effective amount of the compound or salt of Formula (II) of the combination is between about 0.01 to 100 mg/kg per day. 34. The method of any one of claims 1 to 33, wherein the therapeutically effective amount of the compound or salt of Formula (II) in the combination is between about 0.1 to 50 mg/kg per day. 35. The method of any one of claims 1 to 34, wherein the therapeutically effective amount of the immunomodulator inhibitor of the combination is between about 0.01 to 100 mg/kg per day. 36. The method of any one of claims 1 to 35, wherein the therapeutically effective amount of the immunomodulator inhibitor of the combination is between about 0.1 to 50 mg/kg per day.
37. The method of any one of claims 1 to 36, wherein the immunomodulator inhibitor and the compound or salt of Formula (II) are administered on different days. 38. The method of any one of claims 1 to 37, wherein the compound or salt of Formula (II) is administered at a maximum tolerated dose. 39. The method of any one of claims 1 to 38, wherein the immunomodulator inhibitor is administered at a maximum tolerated dose. 40. The method of any one of claims 1 to 39, wherein the immunomodulator inhibitor and the compound or salt of Formula (II) are each administered at a maximum tolerated dose. 41. The method of any one of claims 1 to 40, wherein when M is NR3, Y is O, and R1 is piperazine, the piperazine is substituted with one or more R9, wherein each R9 is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -NO2, =O, =NO(R20), -CN, - NHCN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. 42. The method of any one of claims 1 to 41, wherein the compound or salt is selected from :
Figure imgf000329_0001
,
Figure imgf000330_0001
Figure imgf000331_0001
Figure imgf000332_0001
,
Figure imgf000333_0001
Figure imgf000334_0001
thereof. 43. The method of any one of claims 1 to 41, wherein the compound is selected from:
Figure imgf000334_0002
Figure imgf000335_0001
Figure imgf000336_0001
,
Figure imgf000337_0001
Figure imgf000338_0001
Figure imgf000339_0001
salt of any one thereof. 44. The method of any one of claims 1 to 42, wherein the compound is selected from:
Figure imgf000339_0002
Figure imgf000340_0001
Figure imgf000341_0001
thereof.
45. The method of any one of claims 1 to 43, wherein the compound is selected from:
Figure imgf000342_0001
Figure imgf000343_0001
46. The method of any one of claims 1 to 41, wherein the compound is selected from ,
Figure imgf000344_0001
47. The method of any one of claims 1 to 41, wherein the compound is selected from
Figure imgf000344_0003
. 49. The method of any one of claims 1 to 41, wherein the compound is selected from
Figure imgf000344_0002
salt of any one thereof.
50. The method of any one of claims 1 to 41, wherein the compound is selected from r a salt of any one thereof. ny one of claims 1 to 41, wherein the compound is selected from
Figure imgf000345_0001
salt of any one thereof. 52. The method of any one of claims 1 to 41, wherein the compound is selected from
Figure imgf000345_0002
salt of any one thereof. 53. The method of any one of claims 1 to 51, wherein M is selected from O, NH, and NMe. 54. The method of claim 52, wherein M is O. 55. The method of any one of claims 1 to 51, wherein M is selected from NR3. 56. The method of claim 54, wherein M is selected from NH and NMe. 57. The method of claim 55, wherein M is NMe. 58. The method of any one of claims 1 to 56, wherein B is selected from an optionally substituted 5- to 15-membered heterocycle and optionally substituted C3-C15 carbocycle. 59. The method of claim 57, wherein B is selected from an optionally substituted 8- to 15- membered fused heterocycle and optionally substituted C8-C15 fused carbocycle. 60. The method of claim 59, wherein B is an optionally substituted 8- to 15-membered fused heterocycle. 61. The method of claim 60, wherein B is an optionally substituted unsaturated C8-C15 fused carbocycle.
62. The method of any one of claim 59 to 61, wherein for B, the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15 fused carbocycle are each independently bicyclic or tricyclic. 63. The method of claim 62, wherein for B the heterocycle and carbocycle are each independently bicyclic. 64. The method of claim 62, wherein for B the heterocycle and carbocycle are each independently tricyclic. 65. The method of any one of claims 59 to 64, wherein B is selected from
Figure imgf000346_0001
, ,
Figure imgf000346_0002
, each of which is optionally substituted with one or more substituents. 66. The method of claim 65, wherein B is selected from
Figure imgf000346_0003
,
Figure imgf000346_0004
one or more substituents. 67. The method of claim 66, wherein B is selected from
Figure imgf000346_0005
which is optionally substituted with one or more substituents. 68. The method of any of claims 58 to 67, wherein for B, the one or more optional substituents are independently selected from oxo, -NH2, halogen, C1-C3 alkyl.
69. The method of any one of claims 1 to 68, wherein B is selected from
Figure imgf000347_0001
,
Figure imgf000347_0002
. 70. The method of any of claims 58 to 67, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, C1-C3 alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, -NHCN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. 71. The method of any of claims 58 to 67, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, -OH, -O-C1-C3 haloalkyl, -C(O)NH2, -NH2, =O, -CN, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl. 72. The method of any of claims 58 to 71, wherein B is selected from
Figure imgf000347_0003
,
Figure imgf000347_0004
Figure imgf000348_0001
73. The method of any one of claims 1 to 72, wherein each R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, hydroxyl, halogen. 74. The method of claim 73, wherein each R4 is independently selected from C1-6 alkyl, oxo, and halogen. 75. The method of any one of claims 1 to 74, wherein n is selected from 1 and 2. 76. The method of any one of claims 1 to 75, wherein n is 0. 77. The method of any one of claims 1 to 76, wherein R1 is selected from optionally substituted 5- to 12-membered heterocycle. 78. The method of claim 77, wherein R1 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. 79. The method of claim 78, wherein R1 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. 80. The method of claims 78 or 79, wherein R20 is selected from hydrogen and C1-3 alkyl.
81. The method of any one of claims 77 to 79, wherein the 5- to 12-membered heterocycle of R1 is unsaturated. 82. The method of any one of claims 77 to 79, wherein the 5- to 12-membered heterocycle of R1 is saturated. 83. The method of any one of claims 77 to 79, wherein the 5- to 12-membered heterocycle of R1 is a bridged heterocycle. 84. The method of any one of claims 77 to 83, wherein R1 is selected from
Figure imgf000349_0001
,
Figure imgf000349_0002
85. The method of claim 84, wherein the optional one or more substituents are each independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, =O, -CN, C1-6 hydroxyalkyl, and C1-6 haloalkyl.
86. The method of claim 84, wherein R1 is selected from
Figure imgf000350_0001
,
Figure imgf000350_0002
, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, =O, -CN, C1-6 hydroxyalkyl, and C1-6 haloalkyl.
Figure imgf000350_0003
. 88. The method of any one of claims 77 to 83, wherein R1 is selected from 6- to 8-membered heterocycle, which is optionally substituted. 89. The method of claim 88, wherein R1 is selected from 7-membered saturated heterocycle, 8-membered bridged heterocycle, and 6- to 7-membered unsaturated heterocycle, each of which is optionally substituted. 90. The method of claim 89, wherein R1 is selected from
Figure imgf000350_0004
Figure imgf000350_0005
, each of which is optionally substituted. 91. The method of claim 90, wherein the one or more optional substituents are independently selected from -OH, -CN, oxo, C1-6 cyanoalkyl.
92. The method of claims 90 or 91, wherein R1 is selected from
Figure imgf000351_0001
,
Figure imgf000351_0002
. 93. The method of any one of claims 1 to 76, wherein R1 is selected from an optionally substituted 6- to 7-membered heterocycle. 94. The method of claim 93, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom, and wherein the 6- to 7-membered heterocycle is optionally substituted. 95. The method of claim 94, wherein the 6- to 7-membered heterocycle of R1 is bound to Formula (II) via the only 1 nitrogen atom. 96. The method of any one of claims 93 to 95, wherein R1 is selected from an optionally substituted unsaturated 6-membered heterocycle. 97. The method of any one of claims 93 to 95, wherein R1 is selected from an optionally substituted unsaturated 7-membered heterocycle. 98. The method of any one of claims 93 to 97, wherein R1 is selected from
Figure imgf000351_0003
,
Figure imgf000351_0004
, any of which is optionally substituted. 99. The method of any one of claims 93 to 98, wherein R1 is selected from
Figure imgf000351_0005
, ,
Figure imgf000351_0006
, any of which is optionally substituted.
100. The method of any one of claims 93 to 99, wherein the one or more optional substituents of R1 are each independently selected from halogen, -OR20, -N(R20)2, =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, -NHCN, and C2-6 alkynyl. 101. The method of any one of claims 93 to 100, each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. 102. The method of any one of claims 93 to 101, wherein the one or more optional substituents of R1 are each independently selected from halogen. 103. The method of any one of claims 93 to 102, wherein R1 is selected from
Figure imgf000352_0001
,
Figure imgf000352_0002
104. The method of any one of claims 93 to 101, wherein R1 is selected from
Figure imgf000352_0003
,
Figure imgf000352_0004
, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
105. The method of claim 104, wherein R1 is selected from
Figure imgf000353_0001
, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. 106. The method of claim 105, wherein R1 is selected from
Figure imgf000353_0002
, wherein each is optionally substituted with one or more substituents independently selected from halogen, and C1-6 haloalkyl. 107. The method of claim 106, wherein R1 is selected from
Figure imgf000353_0003
, , ,
Figure imgf000353_0004
108. The method of any one of claims 93 to 101, wherein R1 is selected from , which is optionally substituted with one or more substituents independently selected from halogen, -OH, - NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
Figure imgf000353_0005
109. The method of claim 108, wherein R1 is selected from , which is optionally substituted with one or more substituents independently selected from halogen. 110. The method of claim 109, wherein R1 is selected from
Figure imgf000353_0006
111. The method of claim 93, wherein R1 is selected from 6- to 7-membered heterocycle.
112. The method of claim 111, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur. 113. The method of claim 112, wherein the optionally one or more additional heteroatoms are selected from sulfur. 114. The method of any one of claims 111 to 113, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms. 115. The method of any one of claims 111 to 114, wherein the 6- to 7-membered heterocycle is a non-aromatic 6- to 7-membered heterocycle. 116. The method of any one of claims 112 to 115, wherein the 6- to 7-membered heterocycle of R1 is bound to Formula (II) via the only 1 nitrogen atom. 117. The method of any one of claims 111 to 116, wherein R1 is selected from
Figure imgf000354_0001
, ,
Figure imgf000354_0002
, , , , each of which is optionally substituted. 118. The method of claim 117, wherein the one or more optional substituents of R1 are each independently selected from halogen, -OH, -CN, C1-6 cyanoalkyl, -NHCN, C1-6 alkyl, oxo, and C2-6 alkynyl. 119. The method of claim 113, wherein R1 is selected from an optionally substituted 6- to 10- membered heterocycle. 120. The method of claim 119, wherein R1 is selected from
Figure imgf000354_0003
,
Figure imgf000354_0004
optionally substituted. 121. The method of claim 120, wherein the one or more optional substituents are independently selected from halogen, =O, -OH, -C(O)N(R20)2, C2-6 alkynyl, -NHCN, -CN, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl.
122. The method of claim 121, wherein R1 is selected from
Figure imgf000355_0001
,
Figure imgf000355_0002
123. The method of claim 77, wherein R1 is selected from a 7- to 11-membered spiro heterocycle. 124. The method of claim 123, wherein R1 is selected from a 10-membered spiro heterocycle. 125. The method of claims 123 or 124, wherein the spiro heterocycle has at least 3 nitrogen atoms. 126. The method of claim 125, wherein R1 is selected from
Figure imgf000355_0003
of which is optionally substituted. 127. The method of claim 126, wherein R1 is selected from
Figure imgf000355_0004
of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, =O, -CN, -NHCN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.
128. The method of claim 127, wherein R1 is selected from
Figure imgf000356_0001
,
Figure imgf000356_0002
129. The method of claim 77, wherein R1 is selected from an optionally substituted unsaturated 9- to 11-membered heterocycle. 130. The method of claim 129, wherein R1 is selected from an optionally substituted unsaturated 10-membered heterocycle. 131. The method of claim 130, wherein
Figure imgf000356_0003
, which is optionally substituted. 132. The method of claim 131, wherein
Figure imgf000356_0004
, which is optionally substituted with one or more substituents selected from halogen, -OH, -C(O)N(R20)2, -C(O)OR20, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. or salt of claim 132, wherein R1 is selected from
Figure imgf000356_0005
and
Figure imgf000356_0006
,
Figure imgf000356_0007
, each of which is optionally substituted with one or more substituents selected from halogen, -OH, -N(R20)2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl.
134. The method of claim 77, wherein R1 is selected from an optionally substituted unsaturated 9- to 11-membered heterocycle. 135. The method of claim 134, wherein R1 is selected from an optionally substituted unsaturated 10-membered heterocycle. 136. The method of claim 135, wherein
Figure imgf000357_0001
, which is optionally substituted. 137. The method of claim 136, wherein the one or more optional substituents of R1 are independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)OR20, -C(O)NHOR20, -N(R20)2, - C(O)R20, -NO2, =O, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OR20, and C1-6 alkyl. 138. The method of any one of claims 134 to 137, wherein R1 is selected from
Figure imgf000357_0002
139. The method of any one of claims 134 to 138, wherein R1 is selected from,
Figure imgf000358_0001
,
Figure imgf000359_0001
. 140. The method of any one of claims 134 to 137, wherein the one or more optional substituents of R1 are independently selected from halogen, -OH, -N(R20)2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, -C(O)N(R20)2, C1-6 alkyl, and C2-6 alkynyl. 141. The method of claim 140, wherein the one or more optional substituents of R1 are independently selected from halogen, and -C(O)N(R20)2. 142. The method of claim 141, wherein R1 is selected from
Figure imgf000359_0002
. 143. The method of any one of claims 134 to 137, wherein the one or more optional substituents of R1 are independently selected from halogen, -N(R20)2, -CN, C1-6 alkyl, C1-6 cyanoalkyl, C1-6 alkyl-N(R20)2, C1-6 alkyl-SO2-C1-6 alkyl, C2-6 alkenyl, - C(O)NR20OR20, -C(O)N(R20)2, -C(O)R20, and 5- to 10-membered heterocycle, wherein the 5- to 10-membered heterocycle is optionally substituted independently with one or more R1*, wherein each R1* is independently selected from halogen, -OR20, and C1-6 alkyl. 144. The method of claims 143, wherein the one or more optional substituents of R1 are selected from chlorine, -NH2, -CN, C1 alkyl, C2 alkenyl,
Figure imgf000360_0001
, , ,
Figure imgf000360_0002
. . The method of claim 144, wherein R1 is selected from
Figure imgf000360_0003
,
Figure imgf000360_0004
,
Figure imgf000361_0001
Figure imgf000362_0001
146. The method of any one of claims 1 to 76, wherein R1 is an optionally substituted 12- to 15-membered heterocycle. 147. The method of claim 146, wherein R1 is an optionally substituted 12-membered heterocycle. 148. The method of claim 146, wherein R1 is an optionally substituted 13-membered heterocycle. 149. The method of claim 146, wherein R1 is an optionally substituted 14-membered heterocycle. 150. The method of claim 146, wherein R1 is an optionally substituted 15-membered heterocycle. 151. The method of any one of claims 146 to 150, wherein the heterocycle of R1 is tricyclic. 152. The method of any one of claims 146 to 151, wherein the heterocycle of R1 contains a fused heterocycle. 153. The method of any one of claims 146 to 152, wherein the heterocycle of R1 contains a spiro heterocycle. 154. The method of any one of claims 146 to 153, wherein the heterocycle of R1 contains a fused and spiro-heterocycle. 155. The method of any one of claims 146 to 154, wherein the heterocycle of R1 is an unsaturated heterocycle. 156. The method of any one of claims 146 to 155, wherein the heterocycle of R1 is a non- aromatic heterocycle. 157. The method of any one of claims 146 to 156, wherein the heterocycle of R1 has at least one double bond.
158. The method of any one of claims 146 to 157, wherein the heterocycle of R1 has at least two double bonds. 159. The method of any one of claims 146 to 158, wherein the heterocycle of R1 has two double bonds. 160. The method of any one of claims 146 to 159, wherein R1 is selected from
Figure imgf000363_0001
,
Figure imgf000363_0002
Figure imgf000363_0003
, each of which is optionally substituted with one or more substituents. 161. The method of claim 160, wherein the optional one or more substituents are selected from halogen, -OH, -NHCN, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. 162. The method of claim 161, wherein the optional one or more substituents are selected from halogen, -OH, C1-6 alkyl, and -C(O)N(R20)2. 163. The method of any one of claims 146 to 162, wherein R1 is selected from
Figure imgf000363_0004
,
Figure imgf000364_0001
164. The method of claim 93, wherein R1 is selected from substituted 6- to 7-membered heterocycle, wherein the 6- to 7-membered heterocycle is substituted with at least one -NHCN, and further optionally substituted with one or more C1-6 alkyl. 165. The method of claim 164, wherein R1 is selected from
Figure imgf000364_0002
. 166. The method of any one of claims 1 to 75, wherein R1 is selected from 8- to 10-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)2, -C(O)R20, - C(O)OR20, -NHCN, C1-6 cyanoalkyl, C1-6 alkyl, C2-6 alkynyl, and 5- to 12-membered heterocycle (preferably 5- to 6-membered heterocycle), wherein the 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, C1-6 haloalkyl, and C1-6 alkyl.
1
Figure imgf000365_0001
167. The method of claim 166, wherein R is selected , , and , each of which is optionally substituted.
Figure imgf000365_0002
168. The method of claim 167, wherein R1 is selected , which is optionally substituted. 169. The method of claim 168, wherein R1 is selected from
Figure imgf000365_0003
,
Figure imgf000365_0004
171. The method of any one of claims 1 to 170, wherein Y is O. 172. The method of any one of claims 1 to 171, wherein R2 is -L-heterocycle, optionally substituted with one or more R6. 173. The method of claim 172, wherein L is selected from C1-C4 alkylene. 174. The method of claim 173, wherein L is selected from unsubstituted C1-C4 alkylene. 175. The method of claims 173, wherein each L is independently selected from a C1-C4 alkylene optionally substituted; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl.
176. The method of claims 175, wherein the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6 haloalkyl. 177. The method of claims 1 to 176, wherein Y-R2 is selected from
Figure imgf000366_0001
and
Figure imgf000366_0002
, wherein the heterocycle portion is optionally substituted with one or more R6. 178. The method of claim 177, wherein R6 of R2 is independently selected at each occurrence from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl. 179. The method of claim 178, wherein R6 of R2 is independently selected at each occurrence from C1-C3 alkyl and halogen. 180. The method of claim 177 to 179, wherein Y-R2 is selected from
Figure imgf000366_0003
,
Figure imgf000366_0004
optionally substituted with one or more R6. 182. The method of claim 181, wherein R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, oxo, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. 183. The method of claim 182, wherein R6 is selected from halogen and C1-C3 alkyl.
184. The method of claim 183, wherein Y-R2 is selected from
Figure imgf000367_0001
, ,
Figure imgf000367_0002
186. The method of claim 1 to 171, wherein R2 is selected from -L-heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. 187. The method of claim 186, wherein each L is independently selected from a substituted Cl- C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. 188. The method of claim 187, wherein each L is independently selected from a substituted C1- C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. 189. The method of claim 188, wherein each L is independently selected from a substituted C3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle. 190. The method of claim 189, wherein each L is independently selected from
Figure imgf000367_0003
. 191. The method of claim 190, wherein Y-R2 is
Figure imgf000367_0004
. 192. The method of claim 1 to 176, wherein Y-R2 is selected from
Figure imgf000367_0005
, wherein the heterocycle is optionally substituted. 193. The method of claim 192, wherein the heterocycle is optionally substituted with one or more substituent selected from halogen, hydroxy, C1-C3 alkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, =CH2, oxo, =NO-C1-C3 alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy.
Figure imgf000368_0001
195. The method of any one of claims 1 to 176 or 186 to 190, wherein R2 is selected from -L- N(R21)2. 196. The method of claim 195, wherein L is independently selected from a substituted C1-C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen.
Figure imgf000369_0001
197. The method t of claims 1, 195 or 196, wherein L is F . 198. The method of any one of claims 1, or 195 to 197, wherein R2 is
Figure imgf000369_0002
.
Figure imgf000369_0003
,
Figure imgf000370_0001
Figure imgf000371_0001
,
Figure imgf000372_0001
Figure imgf000373_0001
thereof. 201. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor and a compound of Formula (III):
Figure imgf000374_0001
Formula (III) or a pharmaceutically acceptable salt thereof wherein: R1 is selected from C3-C12 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; R2 is selected from -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L- OC(O)N(R21)2, and L-bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R6; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; n is selected from 0 to 3; each R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, hydroxyl, halogen, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; B is selected from a heterocycle and carbocycle, wherein the heterocycle or carbocycle is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, C1-6 alkyl-N(R20)2, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; Y is selected from a bond, O, S and NR5; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; each R20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R21 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; and each R5 is independently selected from hydrogen or C1-C6 alkyl. 202. The method of claim 201, wherein R2 is selected from L-pyrrolizine, wherein the pyrrolizine is optionally substituted with one or more R6. 203. The method of any one of claims 201 to 202, wherein B is selected from an optionally substituted 5- to 15-membered heterocycle and optionally substituted C3-C15 carbocycle. 204. The method of claim 203, wherein B is selected from an optionally substituted 8- to 15- membered fused heterocycle and optionally substituted C8-C15 fused carbocycle. 205. The method of claim 204, wherein B is selected from an optionally substituted 8- to 15- membered fused heterocycle. 206. The method of claim 204, wherein B is selected from an optionally substituted unsaturated C8-C15 fused carbocycle. 207. The method of any one of claim 203 to 206, wherein for B the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15 fused carbocycle are each bicyclic and tricyclic. 208. The method of claim 207, wherein for B the heterocycle and carbocycle are each independently bicyclic. 209. The method of claim 207, wherein for B the heterocycle and carbocycle are each independently tricyclic. 210. The method of any one of claims 201 to 209, wherein B is selected from
Figure imgf000376_0001
,
Figure imgf000376_0002
, each of which is optionally substituted with one or more substituents.
211. The method of claim 210, wherein B is selected from
Figure imgf000377_0001
,
Figure imgf000377_0002
, each of which is optionally substituted with one or more substituents. 212. The method of claim 211, wherein B is selected from,
Figure imgf000377_0003
, each of which is optionally substituted with one or more substituents. 213. The method of any of claims 201 to 212, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected from oxo, -NH2, halogen, C1-C3 alkyl. 214. The method of any one of claims 201 to 213, wherein B is selected from
Figure imgf000377_0004
,
Figure imgf000377_0005
. 215. The method of any of claims 201 to 212, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, C1-C3 alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, -NHCN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.
216. The method of claim 205, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, - NH2, C1-C3 alkyl, -B(OH)2, -OH, -C(O)NH2, -NH2, =O, -CN, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl. 217. The method of any of claims 215 to 216, wherein B is selected from
Figure imgf000378_0001
,
Figure imgf000378_0002
218. The method of any one of claims 201 to 217, wherein each R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, hydroxyl, halogen. 219. The method of claim 218, wherein each R4 is independently selected from C1-6 alkyl, oxo, and halogen. 220. The method of any one of claims 201 to 219, wherein n is selected from 1 and 2.
221. The method of any one of claims 201 to 219, wherein n is 0. 222. The method of any one of claims 201 to 211, wherein Y is O. 223. The method of any one of claims 201 to 212, wherein R1 is selected from optionally substituted 5- to 12-membered heterocycle. 224. The method of claim 223, wherein R1 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. 225. The method of claim 224, wherein R1 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. 226. The method of claims 224 or 225, wherein R20 is selected from hydrogen and C1-3 alkyl. 227. The method of claims 201 to 226, wherein the 5- to 12-membered heterocycle of R1 is unsaturated. 228. The method of claims 201 to 226, wherein the 5- to 12-membered heterocycle of R1 is saturated. 229. The method of claims 201 to 226, wherein the 5- to 12-membered heterocycle of R1 is bridged. 230. The method of claims 201 to 226, wherein the 5- to 12-membered heterocycle of R1 is a spiro heterocycle. 231. The method of claims 201 to 230, wherein R1 is selected from
Figure imgf000379_0001
, ,
Figure imgf000379_0002
Figure imgf000380_0001
,
Figure imgf000380_0002
, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, =O, -CN, C1-6 hydroxyalkyl, and C1-6 haloalkyl. 232. The method of claim 231, wherein R1 is selected from
Figure imgf000380_0003
,
Figure imgf000380_0004
, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, =O, -CN, C1-6 hydroxyalkyl, and C1-6 haloalkyl. 233. The method of claim 232, wherein R1 is selected from
Figure imgf000380_0005
, ,
Figure imgf000380_0006
. 234. The method of claims 201 to 233, wherein R2 is -L-heterocycle, optionally substituted with one or more R6. 235. The method of claim 234, wherein L is selected from C1-C4 alkylene. 236. The method of claim 235, wherein L is selected from unsubstituted C1-C4 alkylene.
237. The method of any one of claims 234 to 236, wherein Y-R2 is selected from
Figure imgf000381_0001
, wherein the heterocycle portion is optionally substituted with one or more R6. 238. The method of claim 237, wherein R6 of R2 is independently selected at each occurrence from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl. 239. The method of claim 238, wherein R6 of R2 is independently selected at each occurrence from C1-C3 alkyl and halogen. 240. The method of claim 239, wherein Y-R2 is selected from
Figure imgf000381_0002
Figure imgf000381_0003
. 241. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor and a compound of Formula (I):
Figure imgf000381_0004
or a pharmaceutically acceptable salt thereof wherein: R1 is selected from C3-C12 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; Y is selected from a bond, O, S and NR5; R2 is selected from hydrogen, -N(R21)2, -L-N(R21)2, -L-OR21, heterocycle, C1-C6 alkyl, - L-heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R21)2, -L-NHC(=NH)NH2, -L- C(O)N(R21)2, -L-C1-C6 haloalkyl, -L-OR21, -L-NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), - L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L-OC(O)N(R21)2, and -LC(=O)OC1-C6 alkyl, wherein the heterocycle and the aryl portion of -L-NR5C(O)-aryl and the heterocycle portion of -L- heterocycle and the cycloalkyl portion of the -L-cycloalkyl may be optionally substituted with one or more R6, and wherein the aryl or heteroaryl of the -L-aryl and the -L-heteroaryl may be optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; each R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, - OH, -CN, -NO2, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R5 is independently selected from hydrogen or C1-C6 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; each R7 is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R5)2; each R20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, =NH, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R21 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each Q is independently selected from a bond, S, and O; B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, C1-6 alkyl-N(R20)2, C3-C12 carbocycle and 5- to 12- membered heterocycle, wherein C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and wherein B forms a spirocycle with Ring A; and Ring A is selected from a heterocycle and carbocycle, wherein the heterocycle or carbocycle is optionally substituted with one or more substituents selected from R4. 242. The method of claim 241, wherein B is selected from an optionally substituted 5- to 15- membered heterocycle and optionally substituted C3-C15 carbocycle. 243. The method of claim 242, wherein B is selected from an optionally substituted 8- to 15- membered fused heterocycle and optionally substituted C8-C15 fused carbocycle. 244. The method of claim 243, wherein B is an optionally substituted 8- to 15-membered fused heterocycle. 245. The method of claim 243, wherein B is an optionally substituted unsaturated C8-C15 fused carbocycle. 246. The method of any one of claim 241 to 245, wherein for B, the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15 fused carbocycle are each independently bicyclic or tricyclic. 247. The method of claim 246, wherein for B, the heterocycle and carbocycle are each independently bicyclic. 248. The method of claim 246, wherein for B, the heterocycle and carbocycle are each independently tricyclic. 249. The method of any one of claims 241 to 248, wherein B is selected from
Figure imgf000384_0001
,
Figure imgf000384_0002
substituted with one or more substituents. 250. The method of claim 249, wherein B is selected from
Figure imgf000384_0003
, , ,
Figure imgf000384_0004
with one or more substituents.
251. The method of claim 250, wherein B is selected from,
Figure imgf000385_0001
, each of which is optionally substituted with one or more substituents. 252. The method of any of claims 241 to 251, wherein for B, the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH2, halogen, C1-C3 alkyl. 253. The method of any one of claims 241 to 252, wherein B is selected from
Figure imgf000385_0002
,
Figure imgf000385_0003
. 254. The method of any one of claims 241 to 253, wherein each R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, hydroxyl, halogen. 255. The method of claim 254, wherein each R4 is independently selected from C1-6 alkyl, oxo, and halogen. 256. The method of any one of claims 241 to 255, wherein Y is O. 257. The method of any one of claims 241 to 256, wherein R1 is selected from optionally substituted 5- to 5-membered heterocycle. 258. The method of claim 257, wherein R1 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. 259. The method of claim 258, wherein R1 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl.
260. The method of claims 258 to 259, wherein R20 is selected from hydrogen and C1-3 alkyl. 261. The method of any one of claims 241 to 260, wherein the 5- to 12-membered heterocycle of R1 is unsaturated. 262. The method of any one of claims 241 to 260, wherein the 5- to 12-membered heterocycle of R1 is saturated. 263. The method of any one of claims 241 to 260, wherein the 5- to 12-membered heterocycle of R1 is bridged. 264. The method of any one of claims 245 to 260, wherein R1 is selected from ,
Figure imgf000386_0001
independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, =O, -CN, C1-6 hydroxyalkyl, and C1-6 haloalkyl.
265. The method of claim 264, wherein R1 is selected from , , ,
Figure imgf000387_0001
, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, =O, -CN, C1-6 hydroxyalkyl, and C1-6 haloalkyl. 266. The method of claim 265, wherein R1 is selected from
Figure imgf000387_0002
, ,
Figure imgf000387_0003
. 267. The method of any one of claims 241 to 266, wherein R2 is -L-heterocycle, optionally substituted with one or more R6. 268. The method of any one of claims 241 to 267, wherein L is selected from C1-C4 alkylene. 269. The method of claims 267 or 268, wherein L is selected from unsubstituted C1-C4 alkylene. 270. The method of any one of claims 231 to 259, wherein Y-R2 is selected from
Figure imgf000387_0004
wherein the heterocycle portion is optionally substituted with one or more R6. 271. The method of claim 270, wherein R6 of R2 is independently selected at each occurrence from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl. 272. The method of claim 271, wherein R6 of R2 is independently selected at each occurrence from C1-C3 alkyl and halogen.
273. The method of claim 272, wherein Y-R2 is selected from
Figure imgf000388_0001
, ,
Figure imgf000388_0002
. 274. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor and a compound of Formula (II*):
Figure imgf000388_0003
Formula (II*) or a pharmaceutically acceptable salt thereof wherein: M is selected from O, and NR3; R3 is selected from hydrogen, C1-6 alkyl, and C1-6 cyanoalkyl; R1 is selected from a 7- to 10-membered heterocycle, wherein the 7- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; B is selected from C6-C15 carbocycle, wherein the C6-C15 carbocycle is optionally substituted with one or more substituents independently selected from halogen, C1-C3 alkyl, - B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; R2 is selected from -L-heterocycle, wherein the heterocycle of -L-heterocycle is optionally substituted with one or more R6; L is independently selected from a C1-C4 alkylene, wherein the C1-C4 alkylene is optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle; each R20 is independently selected from hydrogen; and C1-6 alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, =NH, C3-12 carbocycle, and 3- to 12-membered heterocycle. 275. The method of claim 274, wherein R1 is selected from an optionally substituted 7- to 10- membered spiro heterocycle and optionally substituted 7- to 10-membered fused heterocycle. 276. The method of claims 274 or 275, wherein the heterocycle of R1 has at least one nitrogen atom. 277. The method of claim 276, wherein the at least one nitrogen at of the heterocycle of R1 is bound to Formula (II*). 278. The method of any one of claims 275 to 277, wherein R1 is selected from an optionally substituted 10-membered spiro heterocycle and optionally substituted 10-membered fused heterocycle. 279. The method of any one of claims 275 to 278, wherein the optional one or more substituents of R1 are independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)OR20, -C(O)NHOR20, - N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkynyl, 5- to 12- membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, and C1-6 alkyl. 280. The method of any one of claims 275 to 279, wherein the optional one or more substituents of R1 are independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)OR20, -C(O)NHOR20, - N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, and C1-6 alkyl. 281. The method of any one of claims 275 to 280, wherein R1 is selected from
Figure imgf000390_0001
, which is substituted. 282. The method of any one of claims 275 to 281, wherein R1 is selected from
Figure imgf000390_0002
substituted with one or more substituents independently selected from halogen, -OH, - S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, - C(O)OR20, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, and C1-6 alkyl. 283. The method of any one of claims 275 to 281, wherein R1 is selected from
Figure imgf000390_0003
, , , ,
Figure imgf000391_0001
284. The method of any one of claims 275 to 282, wherein R1 is selected
Figure imgf000391_0002
,
Figure imgf000391_0003
. 285. The method of claim 278, wherein
Figure imgf000391_0004
. 286. The method of claim 274, wherein M is selected from O. 287. The method of claim 274, wherein M is selected from NCH3 and NCH2CH3. 288. The method of claim 287, wherein M is NMe. 289. The method of any one of claims 224 to 238, wherein the heterocycle of R2 is a saturated heterocycle.
290. The method of claim 289, wherein the heterocycle of R2 is a saturated heterocycle. 291. The method of claim 290, wherein R6 of R2 is independently selected at each occurrence from halogen, =CH2, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl. 292. The method of claim 291, wherein L of R2 is selected from C1-C4 alkylene and
Figure imgf000392_0001
294. The method of any one of claims 274 to 293, wherein B is selected from an optionally substituted C9-C10 fused carbocycle. 295. The method of any one of claims 274 to 294, wherein B is selected from
Figure imgf000392_0002
Figure imgf000392_0003
, each of which is optionally substituted. 296. The method of any one of claims 274 to 295, wherein B is optionally substituted with one or more substituents independently selected from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, - OH, -O-C1-C3 haloalkyl, -C(O)NH2, -NH2, =O, -CN, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl. 297. The method of claim 296, wherein B is optionally substituted with one or more substituents independently selected from halogen. 298. The method of claim 296, wherein B is selected from
Figure imgf000392_0004
. 299. The method of claim 298, wherein
Figure imgf000392_0005
.
300. The method of claim 298, wherein
Figure imgf000393_0001
. 301. The method of claim 274, wherein B is unsubstituted. 302. The method of claim 274, wherein B is substituted. 303. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor and a compound selected from compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 24A, 26, 23A, 23B, 27A, 27B, 28A, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 39A, 39B, 40, 41, 42, 43, 44, 45, 46A, 46B, 47, 48, 49, 50, 51A, 51B, 52, 53, 54, 55, 56, 58, 59, 60, 61, 62, 63, 64, 64B, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, and 103, or a pharmaceutically acceptable salt of anyone thereof. 304. The method of claim 303, wherein the compound is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof. 305. The method of claims 274 or 303, wherein the immunomodulator inhibitor is a PD-1 inhibitor. 306. The method of claim 305, wherein the PD-1 inhibitor is an antibody or antigen-binding fragment. 307. The method of claim 305, wherein the PD-1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, and a biosimilar thereof. 308. The method of claim 305, wherein the PD-1 inhibitor is nivolumab or a biosimilar thereof. 309. The method of claims 307 or 308, wherein the therapeutically effective amount of nivolumab or biosimilar thereof in the combination is about 240 mg administered every two weeks. 310. The method of claims 307 or 308, wherein the therapeutically effective amount of nivolumab, or biosimilar thereof, in the combination is about 480 mg administered every four weeks. 311. The method of claim 307, wherein the PD-1 inhibitor is pembrolizumab or a biosimilar thereof. 312. The method of claim 311, wherein the therapeutically effective amount of pembrolizumab or biosimilar thereof in the combination is about 200 mg administered every three weeks.
313. The method of claim 307, wherein the wherein the PD-1 inhibitor is cemiplimab or a biosimilar thereof. 314. The method of claims 274 or 303, wherein the immunomodulator inhibitor is a PD-L1 inhibitor. 315. The method of claim 314, wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, and a biosimilar thereof. 316. The method of claim 315, wherein the PD-L1 inhibitor is atezolizumab or a biosimilar thereof. 317. The method of claims 274 or 303, wherein the immunomodulator inhibitor is a CTLA-4 inhibitor. 318. The method of any one of claims 274 to 317, wherein the immunomodulator inhibitor is administered orally. 319. The method of any one of claims 274 to 318, wherein the cancer is selected from: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. 320. The method of any one of claims 274 to 319, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer. 321. The method of any one of claims 274 to 320, wherein the cancer is non-small cell lung cancer. 322. The method of any one of claims 274 to 320, wherein the cancer is small cell lung cancer. 323. The method of any one of claims 274 to 320, wherein the cancer is colorectal cancer. 324. The method of any one of claims 274 to 320, wherein the cancer is rectal cancer. 325. The method of any one of claims 274 to 320, wherein the cancer is pancreatic cancer. 326. The method of any one of claims 274 to 320, wherein the cancer is a solid tumor cancer. 327. The method of any one of claims 274 to 326, wherein the cancer is selected from a KRas mutant-associated cancer. 328. The method of any one of claims 274 to 326, wherein the cancer is selected from a KRas wildtype-associated cancer.
329. The method of any one of claims 274 to 326, wherein the cancer is selected from a KRas G12D-associated cancer, a KRas G12V-associated cancer, and a KRas wildtype-associated cancer. 330. The method of any one of claims 274 to 326, wherein the cancer is a KRas G12D- associated cancer. 331. The method of any one of claims 274 to 326, wherein the cancer is a KRas G12V- associated cancer. 332. The method of any one of claims 328 to 329, wherein the KRas wildtype is hyperactivated. 333. The method of any one of claims 274 to 332, wherein the immunomodulator inhibitor synergistically increases the sensitivity of cancer cells to the compound or salt of Formula (II). 334. The method of any one of claims 1 to 40, wherein the compound is selected from
Figure imgf000396_0001
,
Figure imgf000397_0001
Figure imgf000398_0001
,
Figure imgf000399_0001
Figure imgf000400_0001
335. A method of treating cancer in a subject in need thereof, comprising administering to the subject a combination of an immunomodulator inhibitor and a compound represented by the structure of Formula (II):
Figure imgf000401_0001
Formula (II) or a pharmaceutically acceptable salt thereof wherein: M is selected from O, S, SO, SO2, and NR3; R1 is selected from C3-C12 carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl-SO2R20, C1- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; Y is selected from a bond, O, S and NR5; R2 is selected from -L-N(R21)2, -L-OR21, heterocycle, C1-C6 alkyl, -L-heterocycle, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R21)2, -L-C1-C6 haloalkyl, -L- NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L- OC(O)N(R21)2, and -LC(=O)OC1-C6 alkyl, wherein the heterocycle, the aryl portion of -L- NR21C(O)-aryl, the heterocycle portion of -L-heterocycle, the cycloalkyl portion of the -L- cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of the -L- aryl and the heteroaryl portion of the -L-heteroaryl are each optionally substituted with one or more R7, and wherein when Y is a bond, O, or S, R2 is further selected from hydrogen; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkoxyalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; n is selected from 0 to 2; each R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, hydroxyl, halogen, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; each R5 is independently selected from hydrogen or C1-C6 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; each R7 is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R5)2; each R20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, =NH, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R21 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; and B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, C1-6 alkyl-N(R20)2, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. 336. The method of claim 335, wherein the compound is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof. 337. The method of claim 335, wherein the compound is selected from compound 53. 338. The method of claim 335, wherein the compound is selected from compound 61. 339. The method of claim 335, wherein the compound is selected from compound 63. 340. The method of claim 335, wherein the compound is selected from compound 64. 341. The method of claim 335, wherein the compound is selected from compound 69. 342. The method of claim 335, wherein the compound is selected from compound 96. 343. The method of any one of claims 334 to 342, wherein the immunomodulator is selected from a checkpoint inhibitor. 344. The method of any one of claims 334 to 342, wherein the immunomodulator is selected from a PD-1/PD-L1 pathway inhibitor.
345. A method of treating a KRAS associated cancer in a subject in need thereof, wherein the KRAS associated cancer is resistant to treatment with an immunomodulator, comprising administering to the subject a combination of an immunomodulator, or a pharmaceutical composition thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 346. The method of claim 345, wherein the KRas associated cancer is a KRas G12D- associated cancer. 347. The method of claim 345, wherein the KRas associated cancer is a KRas G12V- associated cancer. 348. The method of claim 345, wherein the KRas associated cancer is a KRas wildtype- associated cancer. 349. The method of claim 345, wherein the compound is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof. 350. The method of any one of claims 345 to 349, wherein the immunomodulator is selected from a checkpoint inhibitor. 351. The method of any one of claims 345 to 349, wherein the immunomodulator is selected from a PD-1/PD-L1 pathway inhibitor. 352. A method of suppressing resistance to treatment with an immunomodulator in a subject having a KRas associated cancer that include administering to the subject a combination of an immunomodulator, or a pharmaceutical composition thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 353. The method of claim 352, wherein the KRas associated cancer is a KRas G12D- associated cancer. 354. The method of claim 352, wherein the KRas associated cancer is a KRas G12V- associated cancer. 355. The method of claim 352, wherein the KRas associated cancer is a KRas wildtype- associated cancer. 356. The method of claim 352, wherein the compound is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof. 357. The method of any one of claims 352 to 356, wherein the immunomodulator is selected from a checkpoint inhibitor. 358. The method of any one of claims 352 to 356, wherein the immunomodulator is selected from a PD-1/PD-L1 pathway inhibitor.
359. A method of treating a subject identified or diagnosed as having a KRas associated cancer that include (a) detecting resistance of the KRas associated cancer in the subject to treatment with an immunomodulator that was previously administered to the subject; and (b) after (a), administering to the subject a combination of an immunomodulator and, a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 360. The method of claim 359, wherein the KRas associated cancer is a KRas G12D- associated cancer. 361. The method of claim 359, wherein the KRas associated cancer is a KRas G12V- associated cancer. 362. The method of claim 359, wherein the KRas associated cancer is a KRas wildtype- associated cancer. 363. The method of claim 359, wherein the compound is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof. 364. The method of any one of claims 359 to 363, wherein the immunomodulator is selected from a checkpoint inhibitor. 365. The method of any one of claims 359 to 363, wherein the immunomodulator is selected from a PD-1/PD-L1 pathway inhibitor. 366. A method of treating a subject identified or diagnosed as having a KRas associated cancer and determined to have previously developed resistance to treatment with a KRas associated inhibitor that include administering to the subject a combination of an immunomodulator, or a pharmaceutical composition thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 367. The method of claim 366, wherein the KRas associated cancer is a KRas G12D- associated cancer. 368. The method of claim 366, wherein the KRas associated cancer is a KRas G12V- associated cancer. 369. The method of claim 366, wherein the KRas associated cancer is a KRas wildtype- associated cancer. 370. The method of claim 366, wherein the compound is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof. 371. The method of any one of claims 366 to 370, wherein the immunomodulator is selected from a checkpoint inhibitor.
372. The method of any one of claims 366 to 370, wherein the immunomodulator is selected from a PD-1/PD-L1 pathway inhibitor. 373. A method of treating a subject identified or diagnosed as having a KRas associated cancer, comprising (a) administering a KRas inhibitor as a monotherapy until disease progression, and (b) after (a), administering to the subject a combination of an immunomodulator, or a pharmaceutical composition thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 374. The method of claim 373, wherein the KRas associated cancer is a KRas G12D- associated cancer. 375. The method of claim 373, wherein the KRas associated cancer is a KRas G12V- associated cancer. 376. The method of claim 373, wherein the KRas associated cancer is a KRas wildtype- associated cancer. 377. The method of claim 373, wherein the compound is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof. 378. The method of any one of claims 373 to 377, wherein the immunomodulator is selected from a checkpoint inhibitor. 379. The method of any one of claims 373 to 377, wherein the immunomodulator is selected from a PD-1/PD-L1 pathway inhibitor. 380. A method of treating cancer in a subject in need thereof, comprising administering to the subject a combination of an immunomodulator and a compound of Formula (II), wherein the compound is selected from: compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 24A, 26, 23A, 23B, 27A, 27B, 28A, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 39A, 39B, 40, 41, 42, 43, 44, 45, 46A, 46B, 47, 48, 49, 50, 51A, 51B, 52, 53, 54, 55, 56, 58, 59, 60, 61, 62, 63, 64, 64B, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, and 103, or a pharmaceutically acceptable salt of anyone thereof. 381. A method of treating cancer in a subject in need thereof, comprising administering to the subject a combination of an immunomodulator and a compound of Formula (II), wherein the compound is selected from: compounds 53, 61, 63, 64, 65, 69, and 96, or a pharmaceutically acceptable salt of any one thereof. 382. The method of claim 381, wherein the compound is compound 53. 383. The method of claim 381, wherein the compound is compound 61. 384. The method of claim 381, wherein the compound is compound 63.
385. The method of claim 381, wherein the compound is compound 64. 386. The method of claim 381, wherein the compound is compound 65. 387. The method of claim 381, wherein the compound is compound 69. 388. The method of claim 381, wherein the compound is compound 96. 389. The method of any one of claims 381 to 388, wherein the immunomodulator inhibitor is a PD-1 inhibitor. 390. The method of claim 389, wherein the PD-1 inhibitor is an antibody or antigen-binding fragment. 391. The method of claim 389, wherein the PD-1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, and a biosimilar thereof. 392. The method of claim 389, wherein the PD-1 inhibitor is nivolumab or a biosimilar thereof. 393. The method of claim 389, wherein the PD-1 inhibitor is pembrolizumab or a biosimilar thereof. 394. The method of claim 389, wherein the wherein the PD-1 inhibitor is cemiplimab or a biosimilar thereof. 395. The method of any one of claims 381 to 388, wherein the immunomodulator inhibitor is a PD-L1 inhibitor. 396. The method of claim 395, wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, and a biosimilar thereof. 397. The method of claim 396, wherein the PD-L1 inhibitor is atezolizumab or a biosimilar thereof. 398. The method of any one of claims 381 to 388, wherein the immunomodulator inhibitor is a CTLA-4 inhibitor.
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