Heterocyclic inhibitors of ubiquitin specific protease 1 (USP1) in combination with additional agents for use in the treatment of cancer

Abstract

Described herein are methods of treating cancer using a small molecule ubiquitin specific protease 1 (USP1) inhibitor and an additional agent.

Description

HETEROCYCLIC INHIBITORS OF UBIQUITIN SPECIFIC PROTEASE 1 (USP1) IN COMBINATION WITH ADDITIONAL AGENTS FOR USE IN THE TREATMENT OF CANCERCROSS-REFERENCES TO RELATED APPLICATIONS

[0001] The present application claims priority to International Pat. Appl. No. PCT / CN2024 / 090092, filed on April 26, 2024, which application is incorporated herein by reference in its entirety.BACKGROUND

[0002] Ubiquitin specific protease 1 (USP1) is a well -characterized member of the USP subclass of the deubiquitinating enzymes family, and its expression is dysregulated in many cancers where it acts as an oncogenic driver with roles in various DNA damage repair processes including translesion synthesis and the Fanconi anemia pathway. USP1 cleaves the post- translational modification of ubiquitin from a variety of substrates (e.g., proliferating cell nuclear antigen [PCNA]). It has been previously reported that USP1 plays a critical role in protecting the replication fork in BRCA1 -deficient cells and that knockdown or inhibition of USP1 results in replication fork destabilization via persistent PCNA ubiquitination and decreased viability7of BRC Al -deficient cells. Compounds and pharmaceutical compositions targeting USP1, and methods of treatment for USPl-related diseases and disorders, like certain cancers, have not been widely developed. Therefore, there remains a need to address methods of treating USPl-related diseases.BRIEF DESCRIPTION OF THE DRAWINGS

[0003] The features of the invention are set forth with particularity in the appended claims. A better understanding of the features 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 of which:

[0004] FIG. 1 shows the efficacy of a compound of Formula (IVa-2) and olaparib in MDA- MB-436 xenografts.

[0005] FIG. 2 shows the body weight change after treatment.

[0006] FIG. 3A and FIG. 3B show antitumor efficacy and body weight changes following treatments in ovarian cancer PDX model LD1-2032-361588 in NU / NU mice. FIG. 3A shows the tumor growth curves of LD1-2032-361588 PDX model after treatment in NU / NU mice (n=8). FIG. 3B shows the body weight change rate after treatment.

[0007] FIG. 4 show s colony formation unit (CFU) assay results.

[0008] FIG. 5 shows IC50 values and Synergy Scores of a compound of Formula (IVa-2) and olaparib.

[0009] FIG. 6 shows number of metastatic nodules of treated mice.

[0010] FIG. 7 shows body weight change after administering a compound of Formula (IV a-2) to BALB / c mice bearing orthotopic 4T1 tumors. Data points represent mean body weight.

[0011] FIG. 8 shows that a compound of Formula (IVa-2) combined with paclitaxel inhibits lung cancer metastasis.

[0012] FIG. 9 shows a compound of Formula (IVa-2) combined with anti-PDl inhibits lung cancer metastasis.

[0013] FIG. 10 shows that a compound of Formula (IVa-2) combined with saruparib (AZD5305) inhibits breast cancer.

[0014] FIG. 11 shows that a compound of Formula (IVa-2) combined with irinotecan inhibits breast cancer.

[0015] FIG. 12 shows that a compound of Formula (IVa-2) combined with olaparib inhibits breast cancer.SUMMARY

[0016] In one aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) a compound of Formula (IV a), or a pharmaceutically acceptable salt thereof:wherein,Y1is N or CRY1;Y2is N or CRY2;Y3is N or CRY3;Y4is N or CRY4;R1is hydrogen, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C2-7heterocycloalkyk each of R4and R4is independently selected from hydrogen, halo, -CN, -OR11, -SR11, -N(R12)(RU), optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl; or R4and R4taken together form an oxo; or R4and R4taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; each of R5and R5is independently selected from hydrogen, halo, -CN, -OR11, -SR11, - N(R12)(RU), optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl; or R5and R5taken together form an oxo; or R5and R5taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; each of R6and R6is independently selected from hydrogen, halo, -CN, -OR11, -SR11, - N(R12)(RU), optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C'2-7 heterocycloalkyl: or R6and R6taken together form an oxo; or R6and R6taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; each of R8and R9is independently selected from hydrogen, halo. -CN, optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl; or R8and R9taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; ring A is monocyclic heteroaryl, bicyclic heteroaryl, monocyclic heterocycloalkyl, or bicyclic heterocycloalkyl; each of RAis independently selected from halogen, -NO2, oxo, -CN, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocy cloalkyl. -OR11, -SR11, -N(R12)(Rn), - C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)(Rn), -C(O)N(R12)(Rn), - N(R12)C(O)R12-N(R12)C(O)OR12. -N(R12)C(O)N(R12)(RU), -N(R12)2S(O)2(R12), - S(O)R12, -S(O)2R12, and -S(O)2N(R12)(R11);R11is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C'2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C1-4alkylene-C^-s cycloalkyL optionally substituted -Ci-4 alkylene-C2-7 heterocycloalkyl, optionally substituted -C 1-4 alky lene-phenyl, or optionally substituted -C 1-4 alkyleneheteroaryl; each of R12is independently selected from hydrogen, -NO2, -CN, C1-6 alkyl, Ci-6 aminoalkyl, Ci-e hydroxyalkyl. Ci-ghaloalkyl, C1-6 heteroalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, -CN, Ci-6 alkyl, C1-6 alkoxy, and Ci-6 haloalkyl;RB1is optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl: each of RY1, RY2. RY3and RYIis independently selected from hydrogen, halo, -CN. - NO2, -OR11, -SR11, -N(R12)(Rn), optionally substituted Ci-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6alkynyl, -OR11, -SR11, -N(R12)(Rn), -C(O)R12, -C(O)OR12, -OC(O)R12, - OC(O)N(R12)(R“). -C(O)N(R12)(RU), -N(R12)C(O)R12-N(R12)C(O)OR12, - N(R12)C(O)N(R12)(Rn), -N(R12)S(O)2(R12), -S(O)R12. -S(O)2R12, -S(O)2N(R12)(Rn), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocy clic heteroaryl, and optionally substituted bicyclic heteroaryl; orRY1and R2are taken together with the carbons to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl; orRY?and RY4are taken together with the carbons to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl; m is 0, 1, 2, 3, or 4; and p is 0 or 1; and(b) an additional agent, wherein the combined amount of the compound of Formula (IV a), or a pharmaceutically acceptable salt thereof and the additional agent is therapeutically effective for treating the cancer.

[0017] In another aspect, provided herein is use of a compound of Formula (IV a) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer.wherein the medicament is formulated for being administered in combination with an additional agent.

[0018] In another aspect, provided herein is use of a compound of Formula (IV a) or a pharmaceutically acceptable salt thereof and an additional agent in the manufacture of a medicament for treating cancer.

[0019] In some embodiments, the additional agent is a DNA Damage Response Pathway (DDR) inhibitor, an mTOR inhibitor, an immune checkpoint inhibitor, a cell cycle inhibitor, a radiopharmaceutical agent, an anti-angiogenic agent, an antitubulin agent, a DNA synthesis inhibitor, a DNA alkylating agent, a topoisomerase inhibitor, a chemotherapeutic agent, or any combination thereof.INCORPORATION BY REFERENCE

[0020] 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. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.DETAILED DESCRIPTION

[0021] While various embodiments of the disclosure 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 can occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein can be employed.Definitions

[0022] 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 disclosure belongs. All patents and publications referred to herein are incorporated by reference.

[0023] “Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon mono-radical, and preferably having from one to fifteen carbon atoms (z.e., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (z.e., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (z.e. , Ci-Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (z.e., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (z.e., Ci- C4 alkyl). In other embodiments, an alk l comprises one to three carbon atoms (z.e., C1-C3alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (z.e., C1-C2 alkyl). Whenever it appears herein, a numerical range such as ‘‘C1-C3 alkyl” means that the alky l group consists of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms. In other embodiments, an alkyl comprises one carbon atom (z.e.. Ci alkyl). In other embodiments, an alkyd comprises five to fifteen carbon atoms (z.e., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (z.e., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (z.e. , C2-C5 alkyd). In other embodiments, an alkyd comprises three to five carbon atoms (z.e., C3-C5 alkyl). In certain embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (zz-propyl), 1 -methylethyl (zso-propyl). 1 -butyl (zz-butyl), 1 -methylpropyl (sec-butyl). 2- methylpropyl (iso-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (zz-pentyl). In other embodiments, examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2- methy 1-1 -propyl, 2-methyl-2-propyl, 2-methyl-l -buty l, 3 -methyl- 1 -buty l, 2-methy 1-3 -butyl, 2,2- dimethyl-1 -propyl. 2-methyl-l -penty l. 3-methyl-l-pentyl. 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-I-butyL 2-ethyl-l- butyl, n-butyl, isobutyl, sec-butyl, t-buty l, n-penty 4, isopentyl, neopenty l, tert-amyl, and hexyl, and longer alkyl groups, such as hepty l, octy l, and the like. The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy , aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, - OMe, -NH2, -NO2, or -C=CH. In some embodiments, the alkyd is optionally substituted with oxo, halogen, -CN. -CF3, -OH. or -OMe. In some embodiments, the alkyl is optionally substituted with halogen such as F.

[0024] As used herein, Ci-Cx(or Ci-X) includes C1-C2, C1-C3... Ci-Cx. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alky 4 group, z.e., the alkyl group is selected from among methyl, ethyl, propyl, iso- propy 4, zz-butyl, iso-butyl, sec-buty l, and Cbutyl. Also, by way of example, C0-C2 alkydene includes a direct bond, -CH2-, and -CH2CH2- linkages.

[0025] "Alkoxy” refers to a radical bonded through an oxygen atom of the formula -O- alkyl, where alkyl is an alkyl chain as defined above. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, ary 4, cycloalky 1, heterocycloalkyl, heteroary l, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CFs, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0026] “Alkenyl” refers to an optionally substituted straight or branched hydrocarbon chain radical group containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (z.e., C2-C12 alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (z.e., C2-C8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (z.e., C2-C6 alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (z.e., C2-C4 alkenyl). The group can be in either the cis or trans configuration about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1 -propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” means that the alkenyl group can consist of 2 carbon atoms. 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, ar l, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo. halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (z.e., vinyl), prop-l-enyl (z.e., allyl), but-l-enyl. pent-l-enyl, penta- 1.4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo. halogen, -CN, -CF3. -OH, -OMe, -NH2. or -NO2. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0027] “Alkynyl” refers to an optionally substituted straight or branched hydrocarbon chain radical group containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (z.e.. C2-C12 alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (z.e., C2-C8 alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (z.e. , C2-C6 alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (z. e. , C2-C4 alkynyl). Whenever it appears herein, a numerical range such as “C2- Ce alkynyl” means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms. 4carbon atoms, 5 carbon atoms, or 6 carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propyny 1, butynyl, pentynyl, hexynyl, 2- propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkynyl is optionally substituted with oxo. halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0028] '‘Alkylene” or “alkylene chain” refers to an optionally substituted straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, / 7-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 can be through any two carbons within the chain. In certain embodiments, an alkylene comprises one to ten carbon atoms (i.e., Ci-Cs alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, an alkydene comprises one to four carbon atoms (i.e., C1-C4 alky lene). In other embodiments, an alky dene 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., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., Cs-Cs 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). Unless stated otherwise specifically in the specification, an alkylene group can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, ary l, cycloalkyd, heterocycloalkyl, heteroary l, and the like. In some embodiments, an alkydene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. In some embodiments, the alky dene is -CH2-, - CH2CH2-, or -CH2CH2CH2-. In some embodiments, the alkylene is -CH2-. In some embodiments, the alkylene is -CH2CH2-. In some embodiments, the alkylene is -CH2CH2CH2-.

[0029] "‘Aryl” refers to a radical derived from a hydrocarbon ring system comprising at least one aromatic ring. In some embodiments, an aryl comprises hydrogens and 6 to 30 carbon atoms. The aryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic nng atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene. pyrene, and triphenylene. In some embodiments, the aryl is phenyl. Unless stated otherwise specifically in the specification, an aryl can be optionally substituted, for example, with halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl, alky l, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl. -S(O)2NH-Ci-C6alkyl. and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CFs, -OH, -OMe, -NH2, -NO2, - S(O)2NH2, -S(O)2NHCH3, -S(O)2NHCH2CH3, -S(O)2NHCH(CH3)2, -S(O)2N(CH3)2, or - S(O)2NHC(CH3)3. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3. -OH. or -OMe. In some embodiments, the aryl is optionally substituted with halogen. In some embodiments, the aryl is substituted with alkyl, alkenyl, alkynyl. haloalkyl, or heteroalkyl, wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl is independently unsubstituted, or substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.

[0030] “Aralkyl” refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like.

[0031] “Aralkenyl” refers to a radical of the formula -Rd-aryl where Rdis an alkenylene chain as defined above. " Aralkynyl" refers to a radical of the formula -Re-aryl, where Reis an alkynylene chain as defined above.

[0032] “Carbocycle” refers to a saturated, unsaturated or aromatic rings in which each atom of the ring is carbon. Carbocycle can include 3- to 10-membered monocyclic rings and 6- to 12- membered bicyclic rings (such as spiro, fused, or bridged rings). Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, e.g., phenyl, can 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. In an exemplary embodiment, an aromatic ring, e.g, phenyl, can be fused to a saturated or unsaturated ring, e.g, cyclohexane, cyclopentane, or cyclohexene. A bicyclic carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. A bicyclic carbocycle includes anycombination 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, 6-5 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Exemplary' carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl. and naphthyl. The term “unsaturated carbocycle’7refers to carbocycles with at least one degree of unsaturation and excluding aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene. The term “saturated cycloalkyl” as used herein refers to a saturated carbocycle. Exemplary carbocycles include cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, norborane, and naphthyl. Carbocycles can be optionally substituted by one or more substituents such as those substituents described herein.

[0033] “Cycloalkyd” refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which can include fused (when fused with an ary l or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), bridged, or spiro ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbomyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, - OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl. -CN. -CF3. -OH. or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0034] “Cycloalkylalkyl” refers to a radical of the formula -Rc-cycloalkyl where Rcis an alky lene chain as described above.

[0035] '‘Halo” or “halogen” refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.

[0036] As used herein, the term “haloalkyl” or “haloalkane” refers to an alky l radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, di chloromethyl, bromomethyl. 2,2,2-trifluoroethyl, l-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., tri chloromethane, 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 alky l group is substituted with more than one halogen radicals, each halogen can be independently selected e.g, l-chloro,2-fluoroethane.

[0037] “Fluoroalkyd” 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.

[0038] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyd include, for example, hydroxymethyl, hydroxy ethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl. “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalky l include, for example, aminomethyl, aminoethy l, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0039] The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, - N(alkyl)-), sulfur, or combinations thereof. A heteroalky 1 is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of I to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof wherein the heteroalkyd is attached to the rest of the molecule at a carbon atom of the heteroalkyd. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, or -CH(CH3)OCH3. Unless stated otherwise specifically in the specification, a heteroalkyl isoptionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, - CN, -CF?, -OH, -OMe. -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo. halogen, methyl, ethyl, -CN. -CF3, -OH. or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0040] “HeterocycloalkyF' refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and at least one ring heteroatoms. In some embodiments, a heterocycloalkyl contains from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical can be optionally oxidized; the nitrogen atom can be optionally quatemized.

[0041] Representative heterocycloalkyds include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-C15 heterocycloalkyl), from two to ten carbon atoms (C2-C10 heterocycloalkyl), from two to eight carbon atoms (C2-C8 heterocycloalkyl), from two to six carbon atoms (C2-C6 heterocycloalkyl), from two to five carbon atoms (C2-C5 heterocycloalkyl), or two to four carbon atoms (C2-C4 heterocycloalkyl). In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl. pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3- dihydroisobenzofuran-l-yl, 3-oxo-l,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo- 1,3-dioxol -4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides, and the oligosaccharides. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, aheterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, ary l . cycloalkyd, heterocycloalkyl, heteroar l, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl. -CN. -CF3. -OH. or - OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0042] “Heterocycle” or “heterocyclyl” refers to a saturated, unsaturated or aromatic ring comprising one or more ring heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include e.g., 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings (such as spiro, fused, or bridged rings). Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused, bridged, or spirocyclic ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heterocyclyl radical can be partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl. isothiazolidinyl, isoxazolidinyl, morpholinyl. octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyL 2-oxopiperidinyl. 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term “heterocyclyl” is meant to include heterocyclyl radicals as defined above that are optionally substituted. For example, a heterocyclyl can be optionally substituted by one or more substituents by one or more substituents selected from alky l, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted ary l, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-0Ra, -Rb-0C(0)-Ra, -Rb-OC(O)-ORa, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, - Rb-CN. -Rb-0-Re-C(0)N(Ra)2. -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)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), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substitutedwith halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alky lene or alkenylene chain, and Reis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0043] ■‘Heteroaryl” or “aromatic heterocycle” refers to a ring system radical comprising carbon atom(s) and one or more ring heteroatoms (e.g., selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur), and at least one aromatic ring. In some embodiments, a heteroaryl is a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur. The heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quatemized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl. benzodioxolyl. benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyL benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyL oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-lH-pyrrolyl, phenazinyl. phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl. pyrazolyl, pyridinyl. pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl. quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl. haloalkyl, alkoxy, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a hcteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0044] 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, z.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 can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0045] In some embodiments, substituents can include any substituents described herein, for example: halogen, hydroxy, oxo (=0). thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazino (=N-NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N( Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)Ca)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or(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 can be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine (=N-NH2), SF5, -Rb-0Ra, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-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 Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, and heterocycle, wherein each Ra, valence permitting, can beoptionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyL oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine (=N-NH2), -Rb-0Ra, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2. -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)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 Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain.

[0046] As used in the specification and claims, the singular form “a”, ‘"an” and ‘"the” includes plural references unless the context clearly dictates otherwise.

[0047] 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, -toluenesul Ionic 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, secondary7, 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.

[0048] 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 intrastemal injection and infusion.

[0049] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are. within the scope of soundmedical 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.

[0050] 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 com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) pow dered 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, com 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.

[0051] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder can 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.

[0052] As used herein, the term “synergy ” or “synergistic effect” when used in connection with a combination of agents, means any measured effect of the combination which is greater that the effect predicted from a sum of the effects of the individual agents.

[0053] The terms “treat,” “treating” or “treatment,” as used herein, can 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.

[0054] The terms “effective amount’’ or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g, cancer or an inflammatory’ disease. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms. In some embodiments, an appropriate “effective” amount in any individual case is determined using techniques, such as a dose escalation study.

[0055] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group can be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g, -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g, -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0056] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal.

[0057] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 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, 26, 27, 28. 29. 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, nested sub-ranges that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 can comprise I to 10, 1 to 20, 1 to 30, and I to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.Methods of Treatment of the Disclosure

[0058] Ubiquitin Specific Protease 1 (USP1) is a member of the ubiquitin-specific processing family of proteases. USP1 is a deubiquitinating enz me (“DUB”) and deubiquitinatesits substrates involved in key oncogenic pathways to modulate their functions. Among its roles, USP1 can exhibit DNA-mediated activation at the replication fork, protects the fork, and promote survival in BRC Al -deficient cells. As loss of both USP1 and BRCA1 leads to replication fork degradation, inhibition of USP1 can selectively decrease the viability', or kill, tumor cells with defects in BRCA defects without affecting the survival of cells with normal BRCA function.

[0059] USP1 plays a role in DNA damage repair. USP1 interacts with UAF1 (USP1- associated factor 1) to form a complex that is required for the deubiquitinase activity. The USP1 / UAF1 complex deubiquitinates mono-ubiquitinated PCNA (proliferating cell nuclear antigen) and mono-ubiquitinated FANCD2 (Fanconi anemia group complementation group D2), which are proteins that play important functions in translesion synthesis (TLS) and the Fanconi anemia (FA) pathway, respectively. The USP1 / UAF1 complex also deubiquitinates Fanconi anemia complementation group I (FANCI). These two pathways are essential for repair of DNA damage induced by DNA cross-linking agents, such as cisplatin and mitomycin C (MMC). In cancers with underlying DNA repair vulnerabilities, such as BRCA1 / 2 mutant tumors, USP1 becomes a critical dependency. Therefore, USP1 is a synthetic lethality target for cancer treatment.

[0060] In the United States (US), it has been estimated that inherited BRC Al and BRCA2 mutations are present in 5-10% of breast cancers and 10-15% of ovarian cancers. Breast cancer is the most common cancer in the world and the most common malignancy in women. BRCA1 and BRCA2 can be detected in at least 5% of unselected breast cancer patients and in approximately 30% of patients with a family history of developing breast or ovarian cancer. At present, treatment options including chemotherapy and immune checkpoint inhibitors are limited for breast cancer patients with germline BRCA mutations, more aggressive progression and higher risk of recurrence. Accordingly, new treatments of these cancers are needed.

[0061] In one aspect, the disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject(a) a compound represented by Formula (IV a), or a pharmaceutically acceptable salt thereof:Formula (IV a), wherein,Y1is N or CRY1:Y2is N or CRY2;Y3is N or CRY3;Y4is N or CRY4; each of R1is independently selected from hydrogen, halo, -CN. -OR11, -SR11, -N(R12)(Rn), optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C2-7 heterocycloalkyl; each of R4and R4is independently selected from hydrogen, halo, -CN. -OR11, -SR11, - N(R12)(Rn), optionally substituted C1-6 alkyl, optionally substituted C1-6 alkenyl, optionally substituted C1-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl; or R4and R4taken together form an oxo; or R4and R4taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; each of R5and R5is independently selected from hydrogen, halo, -CN, -OR11, -SR11, - N(R12)(Rn), optionally substituted C1-6 alkyl, optionally substituted Ci-6 alkenyl, optionally substituted C1-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl; or R5and R5taken together form an oxo; or R5and R5taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; each of R6and R6is independently selected from hydrogen, halo, -CN, -OR11, -SR11, - N(R12)(Rn), optionally substituted C1-6 alkyl, optionally substituted C1-6 alkenyl, optionally substituted C1-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl; or R6and R6taken together form an oxo; or R6and R6taken together with the carbon to which they are attached form a 3-6 membered cycloalkyd or 3-6 membered heterocycloalkyl;each of R8and R9is independently selected from hydrogen, halo, -CN, optionally substituted Ci- 6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl; or R8and R9taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl; ring A is monocyclic heteroaiyl, bicyclic heteroaryl, monocyclic heterocycloalkyl, or bicyclic heterocycloalkyl; each of RAis independently selected from halogen, -NO2, oxo, CN, optionally substituted C1-6 alky l, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR11, -SR11, -N(R12)(Rn), -C(O)R12, C(O)OR12, -OC(O)R12, - OC(O)N(R12)(R11), -C(O)N(R12)(RH), -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)C(O)N(R12)(Rn), -N(R12)2S(O)2(R12), -S(O)R12, -S(O)2R12, and -S(O)2N(R12)(Rn);R11is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaiy l, optionally substituted -C1-4 alkylcne-C'3-8 cycloalkyl, optionally substituted -C1-4 alkylene-C2-7 helerocycloalkyl. optionally substituted -C1-4 alkylene-phenyl, or optionally substituted -C1-4 alkylene-heteroaryl; each of R12is independently selected from hydrogen, halogen, -OH, -NO2, CN, C1-6 alkyl, C1-6 aminoalkyl, Ci-6 hydroxyalkyl, Ci-6 haloalkyl, C1-6 heteroalkyl, C3-6 carbocycle, and 3- to 6- membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, CN, Ci-6 alkyl, Ci-6 alkoxy, and Ci-6 haloalkyl;RB1is optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; each of R^1, RY2, R^3and RY4is independently selected from hydrogen, halo, -CN, -NO2, - OR11, -SR11, -N(R12)(Rn), optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, -OR11, -SR11, -N(R12)(R“). -C(O)R12, C(O)OR12, -OC(O)R12, -OC(O)N(R12)(RU), -C(O)N(R12)(RU), - N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)(R11), -N(R12)S(O)2(R12). -S(O)R12. - S(O)2R12, -S(O)2N(R12)(RU), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaiy l, and optionally substituted bicyclic heteroaiy l; orRY1and R2are taken together with the carbons to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl; orRY?and RY4are taken together with the carbons to which they are attached to form an optionally- substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl; m is 0. 1. 2, 3, or 4; and p is 0 or 1; and(b) an additional agent, wherein the combined amount of the compound of Formula (IV a), or a pharmaceutically acceptable salt thereof and the additional agent is therapeutically effective for treating the cancer.

[0062] In some embodiments of Formula (IV a), each of R4and R4is independently selected from hydrogen, halo. -CN. -OR11, -SR11, -N(R12)(Rn), optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl; or R4and R4taken together form an oxo; or R4and R4taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl. In some embodiments, each of R5and R5is independently selected from hydrogen, halo, -CN, -OR11. -SR11, -N(R12)(Rn), optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl; or R5and R5taken together form an oxo; or R5and R5taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl. In some embodiments, each of R6and R6is independently selected from hydrogen, halo, -CN, -OR11, - SR11, -N(R12)(Rn), optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally- substituted C2-7 heterocycloalkyl; or R6and R6taken together form an oxo; or R6and R6taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl. Various USP1 inhibitors, including compounds of Formula (Iva- 1), are disclosed in WO 2023 / 083286 and can be prepared according to the methods disclosed therein.

[0063] In some embodiments, the compound of Formula (IV a) has a structure of Formula (IVa-1),Formula (IVa-1).

[0064] In some embodiments, the compound of Formula (IV a) has a structure of Formula(IVa-2),Formula (IVa-2).

[0065] In some embodiments, the compound of Formula (IV a), (IVa-1), and (IVa-2),Y1is N or CRY1;Y2is N or CRY2;Y3is N or CRY3;Y4is N or CRY4; each of R1is hydrogen, halo, -CN, -OR11, -SR11, -N(R12)(Rn), optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl. optionally substituted C3-8 cycloalkyl, or optionally substituted C2-7 heterocycloalkyl; wherein the alkyl, heteroalkyl, alkenyl, or alkynyl is optionally substituted with one or more substituents independently selected from: halogen, amino, oxo, -OH, - NO2, -CN, and C1-3 alkoxy 1; each of R4and R4is independently selected from hydrogen, halo. -CN. -OR11, -SR11, - N(R12)(Rn), optionally substituted C1-6 alkyl, optionally substituted C1-6 alkenyl, optionally substituted Ci-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl, or R4and R4taken together form an oxo,or R4and R4taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyd, wherein the alky 1, alkeny l, alkynyl, cycloalkyl or heterocy cloalky l is optionally substituted with one or more substituents independently selected from: halogen, amino, -OH, -NO2. oxo, -CN, C1.3 alkoxyl. C1-3 alkyl and C1.3 haloalkyl; each of R5and R5is independently selected from hydrogen, halo, -CN, -OR11, -SR11, - N(R12)(RU), optionally substituted C1-6 alkyd, optionally substituted C1-6 alkenyl, optionally substituted Ci-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl, or R5and R5taken together form an oxo, or R5and R5taken together with the carbon to which they are attached form a 3-6 membered cycloalkyd or 3-6 membered heterocycloalkyd, wherein the alkyd, alkenyl, alky nyl, cycloalkyl or heterocy cloalkyd is optionally substituted with one or more substituents independently selected from: halogen, amino, -OH, -NO2, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl and C1-3 haloalkyl; each of R6and R6is independently selected from hydrogen, halo, -CN, -OR11, -SR11, - N(R12)(RU), optionally substituted C1-6 alkyd, optionally substituted C1-6 alkenyl, optionally substituted C1-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl, or R6and R6taken together form an oxo, or R6and R6taken together with the carbon to which they are attached form a 3-6 membered cycloalkyd or 3-6 membered heterocycloalkyd, wherein the alkyd, alkenyl, alky nyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, amino, -OH, -NO2, oxo, -CN, C1.3 alkoxyl, C1-3 alkyl and C1.3 haloalkyl; each of R8and R9is independently selected from hydrogen, halo, -CN, optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalky 1, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl, or R8and R9taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl, wherein the alk d, alkenyl, alky nyl, cycloalkyl or heterocycloalkyd is optionally substituted with one or more substituents independently selected from: halogen, amino, -OH, -NO2. oxo, -CN, C1-3 alkoxyl. C1-3 alkyl and C1-3 haloalkyl; ring A is monocyclic heteroary dbicyclic heteroaryl, monocyclic heterocycloalkyl, or bicyclic heterocycloalkyd; each ofRAis independently selected from halogen, -NO2, oxo, -CN, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6alkynyl, optionally substituted Ci -6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR11, -SR11, -N(R12)(Rn), - C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)(Rn), -C(O)N(R12)(Rn), - N(R12)C(O)R12-N(R12)C(O)OR12. -N(R12)C(O)N(R12)(RU), -N(R12)2S(O)2(R12), - S(O)R12, -S(O)2R12, and -S(O)2N(R12)(Rn), wherein the alkyl, alkenyl, alkynyl, heteroalkyd, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NO2, oxo, amino. -CN, Ci-e alkoxyl, C1-6 alkyl, Ci-e haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, amino, -NO2, oxo, -CN, Ci-6 alkyd, C1-6 alkoxy, and C 1-6 haloalky 1;R11is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C -8 cycloalky 1, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heleroar I. optionally substituted -C 1-4 alkylene-C3-8 cycloalkyl, optionally substituted -Ci-4 alkylene-C2-7 heterocycloalkyl, optionally substituted -Cw alkylene-phenyL or optionally substituted -C 1-4 alkyleneheteroaryl, wherein the alkyd, alkenyl, alky nyl, heteroalky 1, alkylene, cycloalky 1, heterocycloalky 1, phenyl, or heteroaryl is optionally substituted with one or more substituents independently selected from: halogen, -OH. amino. -NO2, oxo, C1-6 alkoxy, -CN, C1-6 alkyl, and C 1-6 haloalky 1; each of R12is independently selected from hydrogen, halogen, -OH, -NO2, -CN, C1-6 alkyl, C1-6 aminoalkyl, Ci-ehydroxyalkyl, C 1-6 haloalky 1, C 1-6 heteroalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, -CN, C1-6 alkyl, C1-6 alkoxy, and C 1-6 haloalky 1;RB1is optionally substituted C3-8 cycloalkyl, optionally substituted C2.$> heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl, wherein each of the cycloalkyd, heterocycloalkyd, naphthyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from: halogen, -NO2, oxo, -CN, optionally substituted C1-6 alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci -6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, - OR11, -SR11, -N(R12)(Rn), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)(Rn), - C(O)N(R12)(R“). -N(R12)C(O)R12-N(R12)C(O)OR12, -N(R12)C(O)N(R12)(RU). - N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, and -S(O)2N(R12)(Rn), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NO2, amino, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, oxo, -CN, C1-3 alkoxyl, C1-3 alky l and C1-3 haloalkyl; each of RY 1, R3 2. RY3and R34is independently selected from hydrogen, halo, -CN, - NO2, -OR11, -SR11, -N(R12)(Rn), optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, -OR11, -SR11, -N(R12)(Rn), -C(O)R12, -C(O)OR12, -OC(O)R12. - OC(O)N(R12)(Rn), -C(O)N(R12)(Rn), -N(R12)C(O)R12-N(R12)C(O)OR12, - N(R12)C(O)N(R12)(Rn), -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)(Rn), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, and optionally substituted bicyclic heteroaryl. wherein the each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyd, heterocycloalkyd, naphthyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from: halogen, -OH. -NO2, amino, oxo, -CN, Ci-3 alkoxyl. C1-3 alkyl and C1.3 haloalkyl; orRY 1and RY2are taken together with the carbons to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH. amino, -NO2, oxo, C1-6 alkoxy, -CN, C1-6 alkyl, and C 1-6 haloalkyl; orRY3and RY4are taken together with the carbons to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen. -OH. amino. -NO2, oxo. C1-6 alkoxy, -CN, C1-6 alkyl, and C 1-6 haloalkyl; m is 0, 1, 2, 3, or 4; and p is 0 or 1.

[0066] In some embodiments of Formula (IV a), each of R4and R4is independently selected from hydrogen, halo, -CN, -OR11, -SR11, -N(R12)(Rn), optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl, or R4and R4taken together form an oxo, or R4and R4taken together with the carbon to which they are attached form a 3-6 membered cycloalkyd or 3-6 membered heterocycloalky 1, wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, amino, -OH, - NO2, oxo, -CN, C1-3 alkoxyl. C1-3 alkyl and Ci-s haloalkyl.

[0067] In some embodiments of Formula (IV a), each of R5and R5is independently selected from hydrogen, halo, -CN, -OR11, -SR11, -N(R12)(Rn), optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alky nyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl, or R5and R5taken together form an oxo, or R5and R ' taken together with the carbon to which they are attached form a 3-6 membered cycloalkyd or 3-6 membered heterocycloalkyd, wherein the alkyl, alkenyl, alky nyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, amino, -OH, - NO2. oxo, -CN, C1-3 alkoxyl. C1-3 alkyl and Ci-s haloalkyl.

[0068] In some embodiments of Formula (IV a), each of R6and R6is independently selected from hydrogen, halo, -CN, -OR11, -SR11, -N(R12)(Rn), optionally substituted C1-6 alkyd, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alky nyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl, or R6and R6taken together form an oxo, or R6and R6taken together with the carbon to which they are attached form a 3-6 membered cycloalkyd or 3-6 membered heterocycloalkyd, wherein the alkyl, alkenyl, alky nyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, amino, -OH, - NO2, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl and Ci-s haloalkyl.

[0069] In some embodiments of the compound of Formula (IV a), (IVa-1), and (IVa-2),Y1is N or CRY1;Y2is N or CRY2;Y3is N or CRY3;Y4is N or CRY4; each ofR1is hydrogen, -CN, optionally substituted C 1-6 alkyl, optionally substituted C1-6 heteroalkyd, optionally substituted C2-6 alkenyl, and optionally substituted C2-6Z1alkynyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C2-7 heterocycloal kyl; wherein the alkyd, heteroalky l, alkenyl, or alkynyl is optionally substituted with one or more substituents independently selected from: halogen, amino, oxo, -OH, - NO2, -CN, and C1-3 alkoxyl; each of R4and R4is independently selected from hydrogen, -CN, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalky 1, or R4and R4taken together form an oxo, or R4and R4taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, wherein the alky 1, alkeny l, alky nyl, cycloalky l or heterocy cloalky l is optionally substituted with one or more substituents independently selected from: halogen, amino, -OH, -NO2, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl and C1-3 haloalkyl; each of R5and R5is independently selected from hydrogen, -CN, optionally substituted C 1-6 alkyl, optionally substituted C'2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyd, or R5and R5taken together form an oxo, or R5and R5taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, wherein the alky l, alkenyl, alky nyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, amino, -OH, -NO2, oxo, -CN, C1.3 alkoxyl, C1-3 alkyl and C1.3 haloalkyl; each of R6and R6is independently selected from hydrogen, halo, -CN, -OR11, -SR11, - N(R12)(RU), optionally substituted C1-6 alky l, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl, or R6and R6taken together form an oxo, or R6and R6taken together with the carbon to which they are attached form a 3-6 membered cycloalky l or 3-6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alky nyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, amino, -OH, -NO2, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl and C1-3 haloalkyl; each of R8and R9is independently selected from hydrogen, -CN, optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl. or R8and R9taken together with the carbon towhich they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloal kyl, wherein the alky l, alkenyl, alkynyl, cycloalkyl or heterocycloalky l is optionally substituted with one or more substituents independently selected from: halogen, amino, -OH, -NO2. oxo, -CN, C1.3 alkoxyl. C1-3 alkyl and C1.3 haloalkyl; ring A is monocyclic heteroaryl, bicyclic heteroaryl, monocyclic heterocycloalkyl, or bicyclic heterocycloalkyd; each of RAis independently selected from halogen, -NO2, oxo, -CN, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C'2-7 heterocycloalky 1, -OR11, -SR11, -N(R12)(Rn), - C(O)R12, -C(O)OR12. -OC(O)R12, -OC(O)N(R12)(Rn), -C(O)N(R12)(Rn), - N(R12)C(O)R12-N(R12)C(O)OR12. -N(R12)C(O)N(R12)(Rn), -N(R12)2S(O)2(R12), - S(O)R12, -S(O)2R12, and -S(O)2N(R12)(R11), wherein the alkyl, alkenyl, alky nyl, heteroalkyd, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NO2, oxo, amino. -CN, C1-6 alkoxyl, C1-6 alkyl, C 1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, amino, -NO2, oxo, -CN, Ci-6 alkyd, C1-6 alkoxy, and Ci-6 haloalkyl;R11is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-8 cycloalkyd, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 alkylene-C?-8 cycloalkyl, optionally substituted -Ci-4 alkylene-C2-7 heterocycloalkyl, optionally substituted -Cw alkylene-phenyL or optionally substituted -C1-4 alkyleneheteroaryl, wherein the alkyd, alkenyl, alky nyl, heteroalkyd, alkylene, cycloalkyd, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more substituents independently selected from: halogen, -OH. amino. -NO2, oxo. C1-6 alkoxy, -CN, C1-6 alkyl, and C 1-6 haloalky 1; each of R12is independently selected from hydrogen, -NO2, -CN, C1-6 alkyd, Ci-6 aminoalkyl, Ci-e hydroxyalkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-memberedheterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, -CN, C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl;RB1is optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl, wherein each of the cycloalkyd, heterocycloalkyl, naphthyl, phenyl or heteroary l is optionally substituted with one or more substituents independently selected from: halogen, -NO2, oxo, -CN, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, - OR11, -SR11, -N(R12)(Rn), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)(Rn), - C(O)N(R12)(R“). -N(R12)C(O)R12-N(R12)C(O)OR12, -N(R12)C(O)N(R12)(RU). - N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, and -S(O)2N(R12)(Rn), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NO2, amino, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, oxo, -CN, C1-3 alkoxyl, C1-3 alkyd and C1-3 haloalkyl; each of RY1, R^2, RY3and R^4is independently selected from hydrogen, halo, -CN, - NO2, -OR11, -SR11, -N(R12)(Rn), optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, -OR11, -SR11, -N(R12)(Rn), -C(O)R12, -C(O)OR12, -OC(O)R12. - OC(O)N(R12)(Rn), -C(O)N(R12)(Rn), -N(R12)C(O)R12-N(R12)C(O)OR12, - N(R12)C(O)N(R12)(R11), -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)(Rn), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, and optionally substituted bicyclic heteroaryl, wherein the each of the alkyl, alkenyl, alkynyl, heteroalkyd, cycloalkyd, heterocycloalkyd, naphthyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from: halogen, -OH. -NO2, amino, oxo, -CN, C1-3 alkoxyl. C1-3 alkyl and C1-3 haloalkyl; orRY1and RY2are taken together with the carbons to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl,wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, amino, -NO2, oxo, C1-6 alkoxy, -CN, C1-6 alky l, and Ci-e haloalkyl; orRY3and RY4are taken together with the carbons to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, amino, -NO2, oxo, C1-6 alkoxy, -CN, C1-6 alkyl, and Ci-e haloalkyl; m is 0, 1. 2, 3, or 4; and p is 0 or 1.

[0070] In one aspect, the disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject(a) a compound represented by Formula (IV a), or a pharmaceutically acceptable salt thereof:wherein,Y1is N or CRY1;Y2is N or CRY2;Y3is N or CRY3;Y4is N or CRY4;R1is hydrogen, -CN, optionally substituted C1-6 alky l, optionally substituted C1-6 heteroalkyd, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C2-7 heterocycloalkyl; each of R4and R4is independently selected from hydrogen, halo. -CN. -OR11. -SR11, - N(R12)(RU), optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalky 1, and optionally substituted C2-7 heterocycloalkyl; or R4and R4taken together form anoxo; or R4and R4taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; each of R5and R5is independently selected from hydrogen, halo, -CN, -OR11, -SR11, - N(R12)(RU), optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl; or R5and R5taken together form an oxo; or R3and R5taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; each of R6and R6is independently selected from hydrogen, halo. -CN. -OR11, -SR11, - N(R12)(RU), optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyd, and optionally substituted C2-7 heterocycloalky l; or R6and R6taken together form an oxo; or R6and R6taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; each of R8and R9is independently selected from hydrogen, halo, -CN, optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyd, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl; or R8and R9taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; ring A is aryl, monocyclic heteroaryl, bicyclic heteroar l, monocyclic heterocycloalkyl, or bicyclic heterocycloalkyl; each ofRAis independently selected from halogen, -NO2, oxo, -CN, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalky 1, -OR11, -SR11, -N(R12)(Rn), - C(O)R12, -C(O)OR12. -OC(O)R12, -OC(O)N(R12)(Rn), -C(O)N(R12)(Rn). - N(R12)C(O)R12. -N(R12)C(O)OR12, -N(R12)C(O)N(R12)(RU), -N(R12)2S(O)2(R12), - S(O)R12, -S(O)2R12, and -S(O)2N(R12)(R11);R11is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl. optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C1-4 alkylene-Cs-8 cycloalkyl, optionally substituted -C'1-4 alkylene-C'2-7 heterocycloalky I. optionally substituted -C 1-4 alky lene-phenyl, or optionally substituted -C1-4 alkyleneheteroaryl;each of R12is independently selected from hydrogen, -NO2, -CN, C1-6 alkyl, Ci-6 aminoalkyl, Ci-e hydroxyalkyl, Ci-ehaloalkyl, C 1-6 heteroalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, -CN, Ci-6 alkyl, C1-6 alkoxy, and Ci-6 haloalkyl;RB1is optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroar l, or optionally substituted bicyclic heteroaryl: each of RY 1, R3 2. RY3and R34is independently selected from hydrogen, halo, -CN, - NO2, -OR11, -SR11, -N(R12)(Rn), optionally substituted Ci-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, -OR11, -SR11, -N(R12)(Rn), -C(O)R12, -C(O)OR12, -OC(O)R12. - OC(O)N(R12)(Rn), -C(O)N(R12)(Rn), -N(R12)C(O)R12-N(R12)C(O)OR12, - N(R12)C(O)N(R12)(Rn), -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)(Rn), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, and optionally substituted bicyclic heteroaryl: orRY1and RY2are taken together with the carbons to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C 2-9 heterocycloalkyl; orRY3and R34are taken together with the carbons to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl; m is 0, 1, 2, 3, or 4; and p is 0 or 1; and(b) an additional agent, wherein the combined amount of the compound of Formula (IV a), or a pharmaceutically acceptable salt thereof and the additional agent is therapeutically effective for treating the cancer.

[0071] In some embodiments of Formula (IV a). (IVa-1), and (IVa-2), ring A is aryl, monocyclic heteroaryl, bicyclic heteroaryl, monocyclic heterocycloalkyl, or bicyclicat least one of Y1, Y2, Y3, and Y4is N; andRR1is optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl.

[0072] In some embodiments of Formula (IV a), (IVa-1), and (IVa-2), ring A is aryl. In some embodiments, ring A is phenyl.

[0073] In some embodiments of Formula (IV a), (IV a- 1), and (IVa-2),. In some embodiments of Formulas (IV a), (IVa-1), and (IVa-2), ring A is unsubstituted aryl (e.g., phenyl). In some embodiments of Formulas (IV a), (IVa-1), and (IVa-2), ring A is aryl (e.g., phenyl) that is optionally substituted with 1 to 5 RA. In some embodiments ofFormulas (IVa), (IVa-1), and (IVa-2), ring A is aryl (e.g , phenyl) that is substituted with 1 RA. In some embodiments of Formulas (IVa), (IVa-1), and (IVa-2), ring A is aryl (e.g., phenyl) that is substituted with 2 RA. In some embodiments of Formulas (IVa), (IVa-1), and (IVa-2), ring A is aryl (e.g., phenyl) that is substituted with 3 RA. In some embodiments of Formulas (IVa), (IVa-1), and (IVa-2). ring A is aryl (e.g., phenyl) that is substituted with 4 RA. In some embodiments of Formulas (IVa), (IVa-1), and (IVa-2), ring A is aryl (e.g., phenyl) that is substituted with 5 RA.

[0074] In some embodiments of Formulas (IVa), (IVa-1), and (IVa-2), at least one of Y1, Y2, Y3. and Y4is N. In some embodiments, one of Y1. Y2. Y3, and Y4is N. In some embodiments, two of Y1, Y2, Y3, and Y4are N. In some embodiments, three of Y1, Y2, Y3, and Y4are N. In some embodiments of Formulas (IVa), (IVa-1), and (IVa-2), RB1is optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl. In some embodiments, RB1is optionally substituted monocyclic heteroaryl (e.g., 5 membered heteroaryl). In some embodiments, RB1is substituted monocyclic heteroaryl.

[0075] In some embodiments of Formulas (IVa), (IVa-1), and (IVa-2), each RAis independently selected from halogen, -NO2, oxo, -CN, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl. - SR11, -N(R12)(Rn), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)(RU), -C(O)N(R12)(RU), - N(R12)C(O)R12-N(R12)C(O)OR12, -N(R12)C(O)N(R12)(RU), -N(R12)2S(O)2(R12), -S(O)R12, - S(O)2R12, and -S(O)2N(R12)(R11). In some embodiments, RAis not Ci-6 alkoxyl. In some embodiments, RAis not Cl. In some embodiments, RAis not halogen.

[0076] In some embodiments, the compound of Formula (IVa) is represented by Formula (IVa-1), or a pharmaceutically acceptable salt thereof:Formula (IVa-1).

[0077] In some embodiments, the compound of Formula (IVa) is represented by Formula(IVa-2), or a pharmaceutically acceptable salt thereof:Formula (IVa-2).

[0078] In some embodiments of Formula (IV a), (IVa-1), and (IVa-2), each of R1is hydrogen, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C2-7 heterocycloalkyl.

[0079] In some embodiments of Formula (IV a) and (IVa-1), each of R4and R4is independently selected from hydrogen, -CN, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C'2-7 heterocycloalkyl; or R4and R4taken together form an oxo; or R4and R4taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl.

[0080] In some embodiments of Formula (IV a) and (IVa-1), each of R5and R5is independently selected from hydrogen, -CN, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl. optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl; or R3and R3taken together form an oxo; or R5and R5taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl.

[0081] In some embodiments of Formula (IV a) and (IVa-1), each of R6and R6is independently selected from hydrogen, -CN, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyd; or R6and R6taken together form an oxo; or R6and R6taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl.

[0082] In some embodiments of Formula (IV a), each of R8and R9is independently selected from hydrogen, -CN, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl; or R8and R9taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl.

[0083] In some embodiments of Formula (IV a), (IV a- 1), and (IVa-2), each of R12is independently selected from hydrogen, -NO2, CN, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, Ci-6 heteroalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen. -OH. oxo, amino, -NO2, CN, C1-6 alkyl, C1-6 alkoxy, and Ci-6 haloalkyl.

[0084] In some embodiments of Formula (IV a), (IVa-1), and (IVa-2), ring A is 3-6 membered monocyclic heterocycloalkyl containing 1-4 heteroatoms selected from O, S, N, P, and Si. In some embodiments, ring A is fused, spiro, or bridged bicyclic heterocycloalkyl containing 1-4 heteroatoms selected from O, S, N, P, and Si. In some embodiments, ring A is a 5 membered monocyclic heteroaryl. In some embodiments, ring A is a 6 membered monocyclic heteroaryl. In some embodiments, ring A is a 6 membered monocyclic heteroaryl containing 1-3 heteroatoms. In some embodiments, ring A is pyridine, pyrimidine, pyrazine, pyridazine, triazine, imidazole, pyrazole, triazole, oxazole, isoxazole, or thiophene. In some embodiments.some embodiments, ring A is bicyclic heteroaryl. In some embodiments, ring A is fused 5-6, 6-6, or 6-5 bicyclic heteroaryl.

[0085] In some embodiments of Formula (IV a), (IV a- 1), and (IVa-2), each RAis independently selected from halogen, -NO2, oxo, -CN, optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR11, -SR11, -N(R12)(R11), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)(Rn), -C(O)N(R12)(RU), -N(R12)C(O)R12-N(R12)C(O)OR12, - N(R12)C(O)N(R12)(Rn), -N(R12)2S(O)2(R12), -S(O)R12, -S(O)2R12, and -S(O)2N(R12)(Rn). In some embodiments of Formula (IV a), (IVa-1), and (IVa-2). each RAis independently selected from halogen, OH. -NO2, oxo. -CN. C1-6 alkyl, Ci-6 alkoxyl. Ci-s haloalkyl, C1-6 heteroalkyl, and C3-6 cycloalkyl. In some embodiments, each RAis independently selected from halogen, C1-6 alkyd, C 1-6 alkoxyl, C1-6 haloalky 1, and C3-6 cycloalkyl. In some embodiments, each RAis independently selected from Ci-6 alkyl, Ci-6 alkoxyl, C 1-6 haloalkoxyl, C1-6 haloalkyl, and C3-6 cycloalkyl. In some embodiments, each RAis independently selected from halogen, Ci-6 alkyl, Ci-6 alkoxyl, and C3-6 cycloalkyl, wherein the alkyl, alkoxyl and cycloalkyl is optionally substituted with one or more halogen (e.g, 1-3 fluorine). In some embodiments, each RAis independently selected from methyl, ethyl, propyl, buty l, -O-methy 1, -O-ethyl, -O-propy 1, -O- butyl, cyclopropy l. CN, OH, -O-CHF2, -O-CH2F, CHF2, CH2F, and CF3. In some embodiments, RAis halogen. In some embodiments, RAis -NO2. In some embodiments, RAis oxo. In some embodiments, RAis -CN. In some embodiments, RAis optionally7substituted Ci-6 alkyl. In some embodiments, RAis Ci-alky 1. In some embodiments, RAis C2 alkyd. In some embodiments, RAis C3 alkyl. In some embodiments, RAis optionally substituted C 1-6 heteroalkyl. In some embodiments, RAis C3 heteroalkyl. In some embodiments, RAis optionally substituted C3-8 cycloalky 1. In some embodiments, RAis C3 cycloalkyl. In some embodiments, RAis optionally substituted C2-7 heterocycloalkyl. In some embodiments, RAis C2 heterocycloalky7!. In someembodiments, RAis -OR11. In some embodiments, RAis -SR11. In some embodiments, RAis - N(R12)(Rn). In some embodiments, RAis -C(O)R12. In some embodiments, RAis -C(O)OR12. In some embodiments, RAis -OC(O)R12. In some embodiments, RAis -OC(O)N(R12)(Rn). In some embodiments, RAis -C(O)N(R12)(Rn) In some embodiments. RAis -N(R12)C(O)R12- N(R12)C(O)OR12. In some embodiments, RAis -N(R12)C(O)N(R12)(Rn). In some embodiments. RAis -N(R12)2S(O)2(R12). In some embodiments, RAis -S(O)R12. In some embodiments, RAis - S(O)2R12. In some embodiments, RAis -S(O)2N(R12)(Rn).

[0086] In some embodiments of Formula (IV a), (IV a- 1), and (IVa-2), RAis independently substituted with one or more substituents independently selected from: halogen, -OH, -NO2, amino, -CN, C1-6 alkoxyl, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, amino, - NO2, oxo, -CN, C1-6 alkyl, C1-6 alkoxy, and C 1-6 haloalkyl.

[0088] In some embodiments of Formula (IVa), (IVa-1), and (IVa-2), p is 1. In some embodiments, p is 0.

[0089] In some embodiments of Formula (IVa), (IVa-1), and (IVa-2), each of R8and R9is independently selected from hydrogen, halo, -CN, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl. In some embodiments of Formula (IVa), (IVa-1), and (IVa-2), each of R8and R9is independently selected from hydrogen, -CN, optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl. In some embodiments. In some embodiments, R8and R9taken together with the carbon to which they' are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl.

[0090] In some embodiments of Formula (IVa), (IVa-1), and (IVa-2), RB1is optionally substituted C3-8 cycloalkyl or optionally substituted phenyl. In some embodiments, RB1is optionally substituted C2-9 heterocycloalkyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl, each of which containing 1-4 heteroatoms selected from O, S, N, P, and Si. In some embodiments, RB1is optionally substituted C3-8 cycloalkyl. In some embodiments, RB1is C3 cycloalkyl. In some embodiments, RB1is C5 cycloalkyd. In some embodiments, RB1is Ce cycloalkyl. In some embodiments, RB1is optionally substituted phenyl. In some embodiments, RB1is optionally substituted C2-9 heterocycloalkyl. In some embodiments, RB1is C3 heterocycloalkyl. In some embodiments, RB1is C5 heterocycloalkyl. In some embodiments, RB1is Ce heterocycloalkyl. In some embodiments, RB1is optionally substituted monocyclic heteroaryl. In some embodiments, RB1is optionally substituted bicyclic heteroaryl. In some embodiments, RB1is imidazole, pyrazole, triazole, or tetrazole, each of which optionally substituted. In some embodiments, RB1is imidazole. In some embodiments, RB1is pyrazole. In some embodiments, RB1is triazole. In some embodiments, RB1is tetrazole. In some embodiments, RB1is optionally substituted fused 5-6, 6-6 or 6-5 heteroaryl. In some embodiments, RB1is optionally substituted with one or more substituents independently selectedfrom halogen, -NO2, oxo, -CN, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, - OR11, -SR11, -N(R12)(Rn), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)(Rn), - C(O)N(R12)(Rn), -N(R12)C(O)R12-N(R12)C(O)OR12, -N(R12)C(O)N(R12)(RU), - N(R12)S(O)2(R12), -S(O)R12. -S(O)2R12, and -S(O)2N(R12)(Rn), wherein the alkyl, alkenyl, alkynyl, heteroalk l. cycloalkyl, or heterocycloalkyl is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NO2, amino, oxo, -CN, C1-3 alkoxyl, C1-3 alkyl and C1-3 haloalkyl. In some embodiments, RB1is optionally substituted with one or more substituents independently selected from halogen. -OR11, -NO2. oxo, -CN, optionally substituted C1-6 haloalkyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 aminoalkyl, optionally substituted C 1-6 hydroxy alkyd, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl. In some embodiments, RB1is optionally substituted with one or more substituents independently selected from halogen, -OR11, -NO2, oxo, -CN, C1-3 haloalkyl, C1-3 alkyl, C1-3 aminoalkyl, C1-3 hydroxyalkyl, optionally substituted C 1-4 heteroalkyl (e.g., -CH2C(=O)N(CH3)2), optionally substituted C3-6 cycloalkyl, and optionally substituted C2-5 heterocycloalkyl. In some embodiments, RB1is optionally substituted with one or more substituents independently selected from halogen, oxo. -CN. C1-3 haloalkyl, C1-3 alkyl. C1-3 aminoalkyl, C1-3 hydroxyalkyl, C3-6 cycloalkyl, and C2-5 heterocycloalkyl. In some embodiments, RB1is optionally substituted with one or more substituents (e.g., 1, 2 or 3) independently selected from C1-3 haloalkyl and C1-3 alky l. In some embodiments, RB1is substituted with halogen. In some embodiments, RB1is substituted with -OR11. In some embodiments, RB1is substituted with -NO2. In some embodiments, RB1is substituted with oxo. In some embodiments, RB1is substituted with -CN. In some embodiments, RB1is substituted with optionally substituted C1-6 haloalkyl. In some embodiments, RB1is substituted with optionally substituted C1-6 alky l. In some embodiments, RB1is substituted with optionally substituted Ci-6 aminoalkyl.

[0091] In some embodiments of Formula (IV a), (IV a- 1), and (IVa-2), RB1is

[0092] In some embodiments of Formula (IV a). (IV a- 1), and (IVa-2), RB1is

[0093] In some embodiments of a compound of Formula (IV a), (IVa-1), and (IVa-2), Y1is N or CR \ In some embodiments. Y1is N. In some embodiments, Y1is CR \ In some embodiments, Y2is N. In some embodiments. Y2is CRY2. In some embodiments, Y3is N. In some embodiments, Y3is CRY3. In some embodiments, Y4is N. In some embodiments, Y4is CRY4.

[0094] In some embodiments of a compound of Formula (IV a). (IVa-1), and (IVa-2), R1is hydrogen, halo, -CN, -OR11. -SR11, -N(R12)2, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl. In some embodiments of a compound of Formula (IV a), (IVa-1), and (IVa-2), R1is hydrogen, -CN, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl,optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl. In some embodiments, R1is hydrogen. In some embodiments, R1is halo. In some embodiments, R1is - CN. In some embodiments, R1is -OR11. In some embodiments, R1is -SR11. In some embodiments, R1is -N(R12)2. In some embodiments, R1is optionally substituted C1-6 alkyl. In some embodiments, R1is C1-3 alkyl. In some embodiments. R1is methyl. In some embodiments. R1is ethyl. In some embodiments, R1is CD In some embodiments, R1is optionally substituted C1-6 heteroalkyl. In some embodiments, R1is C1-3 heteroalkyl. In some embodiments, R1is optionally substituted C2-6 alkenyl. In some embodiments, R1is C2-3 alkenyl. In some embodiments, R1is optionally substituted C2-6 alkynyl.

[0095] In some embodiments of a compound of Formula (IVa), (IVa-1), and (IVa-2), R1is hydrogen, halo, -CN, -OR11, -SR11, -N(R12)(Rn), optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C2-7 heterocycloalkyl. In some embodiments of a compound of Formula (IVa), (IVa-1), and (IVa-2), R1is hydrogen, -CN, optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C2-7 heterocycloalkyl. In some embodiments, R1is hydrogen. In some embodiments, R1is halo. In some embodiments, R1is -CN. In some embodiments. R1is -OR11. In some embodiments, R1is -SR11. In some embodiments, R1is -N(R12)(Rn). In some embodiments, R1is optionally substituted C1-6 alkyl. In some embodiments, R1is optionally substituted C1-6 heteroalkyl. In some embodiments, R1is optionally substituted C2-6 alkenyl. In some embodiments, R1is optionally substituted C2-6 alkynyl. In some embodiments, R1is optionally substituted C3-8 cycloalkyl. In some embodiments, R1is optionally substituted C2-7 heterocycloalkyl.

[0096] In some embodiments of a compound of Formula (IVa) or (IVa-1), each of R4and R4is independently selected from hydrogen, halo, -CN, -OR11. -SR11, -N(R12)(Rn), optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C 2-7 heterocycloalkyl; or R4and R4taken together form an oxo; or R4and R4taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl. In some embodiments of a compound of Formula (IVa) or (IVa-1), each of R4and R4is independently selected from hydrogen, -CN, optionally substituted C 1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl; or R4and R4taken together form an oxo; or R4and R4taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6membered heterocycloalkyl. In some embodiments, R4is hydrogen. In some embodiments, R4is halo. In some embodiments, R4is -CN. In some embodiments, R4is -OR11. In some embodiments, R4is -SR11. In some embodiments, R4is -N(R12)(Rn). In some embodiments, R4is optionally substituted Ci-6 alkyl. In some embodiments, R4is optionally substituted Ci-6 alkenyl. In some embodiments, R4is optionally substituted C2-6 alkenyl. In some embodiments, R4is optionally substituted C1-6 alkynyl. In some embodiments, R4is optionally substituted C2-6 alkynyl. In some embodiments, R4is optionally substituted C3-8 cycloalkyd. In some embodiments, R4is optionally substituted C2-7 heterocycloalky l. In some embodiments, R4is hydrogen. In some embodiments, R4is halo. In some embodiments, R4is -CN. In some embodiments, R4is -OR11. In some embodiments, R4is -SR11. In some embodiments, R4is - N(R12)(Rn). In some embodiments, R4is optionally substituted Ci-6 alkyl. In some embodiments, R4is optionally substituted Ci-6 alkenyl. In some embodiments, R4is optionally substituted Ci-6 alkynyl. In some embodiments, R4is optionally substituted C2-6 alkenyl. In some embodiments, R4is optionally substituted C2-6 alkynyl. In some embodiments, R4is optionally substituted C3-8 cycloalkyl. In some embodiments, R4is and optionally substituted C2-7 heterocycloalkyl. In some embodiments, R4and R4taken together form an oxo. In some embodiments, R4and R4taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl.

[0097] In some embodiments of a compound of Formula (IV a) or (IVa-1)), each of R5and R5is independently selected from hydrogen, halo, -CN, -OR11, -SR11, -N(R12)(Rn), optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl. In some embodiments of a compound of Formula (IV a) or (IVa-1)), each of R5and R5is independently selected from hydrogen, -CN, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally- substituted C2-7 heterocycloalkyl. In some embodiments, R5is hydrogen. In some embodiments, R5is halo. In some embodiments, R5is -CN. In some embodiments, R5is -OR11. In some embodiments, R5is -SR11. In some embodiments, R5is -N(R12)(Rn). In some embodiments, R5is optionally substituted Ci-6 alkyl. In some embodiments, R5is optionally substituted Ci-6 alkenyl. In some embodiments, R5is optionally substituted Ci-6 alkynyl. In some embodiments, R5is optionally substituted C2-6 alkenyl. In some embodiments, R5is optionally substituted C2-6 alkynyl. In some embodiments, R5is optionally substituted C3-8 cycloalkyl. In some embodiments, R5is optionally substituted C 2-7 heterocycloalkyl. In some embodiments, R5is hydrogen. In some embodiments, R5is halo. In some embodiments, R5is -CN. In some embodiments, R5is -OR11. In some embodiments, R5is -SR11. In some embodiments. R5is -N(R12)(R11). In some embodiments, R ' is optionally substituted Ci-6 alkyl. In some embodiments, R5is optionally substituted Ci-6 alkenyl. In some embodiments, R5is optionally substituted Ci-6 alkynyl. In some embodiments, R5is optionally substituted C2-6 alkeny l. In some embodiments, R5is optionally substituted C2-6 alkynyl. In some embodiments, R5is optionally substituted C3-8 cycloalkyl. In some embodiments. R5is and optionally substituted C2-7 heterocycloalkyl. In some embodiments, R5and R5taken together form an oxo. In some embodiments, R5and R5taken together with the carbon to which they are attached form a 3-6 membered cy cloalkyl or 3-6 membered heterocycloalkyl.

[0098] In some embodiments of a compound of Formula (IV a) or (IVa-1), each of R6and R6is independently selected from hydrogen, halo, -CN, -OR11, -SR11, -N(R12)(R11), optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl. In some embodiments of a compound of Formula (IV a) or (IVa-1)), each of R6and R6is independently selected from hydrogen, -CN, optionally substituted C 1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl. In some embodiments, R6is hydrogen. In some embodiments, R6is halo. In some embodiments, R6is -CN. In some embodiments, R6is -OR11. In some embodiments, R6is -SR11. In some embodiments. R6is -N(R12)(Rn). In some embodiments. R6is optionally substituted Ci-6 alkyl. In some embodiments, R6is optionally substituted C1-6 alkenyl. In some embodiments, R6is optionally substituted C1-6 alkynyl. In some embodiments, R6is optionally substituted C2-6 alkenyl. In some embodiments, R6is optionally substituted C2-6 alkynyl. In some embodiments, R6is optionally substituted C3-8 cycloalkyl. In some embodiments, R6is optionally substituted C2-7 heterocycloalkyl. In some embodiments, R6is hydrogen. In some embodiments, R6is halo. In some embodiments, R6is -CN. In some embodiments, R6is -OR11. In some embodiments, R6is -SR11. In some embodiments, R6is - N(R12)(Rn). In some embodiments, R6is optionally substituted Ci-6 alkyl. In some embodiments, R6is optionally substituted Ci-6 alkenyl. In some embodiments, R6is optionally substituted Ci-6 alkynyl. In some embodiments, R6is optionally substituted C2-6 alkenyl. In some embodiments, R6is optionally substituted C2-6 alkynyl. In some embodiments, R6is optionally substituted C3-8 cycloalkyl. In some embodiments. R6is and optionally substituted C2-7 heterocycloalkyl. In some embodiments, R6and R6taken together form an oxo. In some embodiments, R6and R6taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl.

[0099] In some embodiments of a compound of Formula (IV a), (IVa-1), and (IVa-2), each of R8and R9is independently selected from hydrogen, halo, -CN. optionally substituted Ci-6alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl. In some embodiments of a compound of Formula (IV a), (IVa-1), and (IVa-2), each of R8and R9is independently selected from hydrogen, -CN, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl. In some embodiments, R8is hydrogen. In some embodiments, R8is halo. In some embodiments, R8is -CN. In some embodiments, R8is optionally substituted C1-6 alkyl. In some embodiments, R8is optionally substituted Ci-6 heteroalkyl. In some embodiments, R8is optionally substituted C2-6 alkenyl. In some embodiments, R8is optionally substituted C2-6 alkynyl. In some embodiments, R9is hydrogen. In some embodiments, R9is halo. In some embodiments, R9is -CN. In some embodiments, R9is optionally substituted Ci-6 alkyl. In some embodiments, R9is optionally substituted Ci-6 heteroalkyl. In some embodiments, R9is optionally substituted C2-6 alkenyl. In some embodiments, R9is optionally substituted C2-6 alkynyl. In some embodiments, R8and R9taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyd or heterocycloalkyl.

[0100] In some embodiments of a compound of Formula (IV a), (IVa-1), and (IVa-2), ring A is monocyclic heteroaiyl, bicyclic heteroaryl, monocyclic heterocycloalkyl, or bicyclic heterocycloalkyl. In some embodiments, ring A is monocyclic heteroaryl. In some embodiments, ring A is bicyclic heteroaryl. In some embodiments, ring A is monocyclic heterocycloalkyl. In some embodiments, ring A is bicyclic heterocycloalkyl.

[0101] In some embodiments of a compound of Formula (IV a), (IVa-1), and (IVa-2), each of RAis independently selected from halogen. -NO2, oxo. CN, optionally’ substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, - OR11, -SR11, -N(R12)(Rn), -C(O)R12, C(O)OR12, -OC(O)R12, -OC(O)N(R12)(Rn), - C(O)N(R12)(Rn), -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)(RU), - N(R12)2S(O)2(R12), -S(O)R12, -S(O)2R12, and -S(O)2N(R12)(Rn). In some embodiments, RAis halogen. In some embodiments, RAis -NO2. In some embodiments, RAis oxo. In some embodiments, RAis CN. In some embodiments, RAis optionally substituted Ci-6 alkyl. In some embodiments, RAis optionally substituted C1-3 alkyl. In some embodiments, RAis methyl, ethyl, propyl. Ao-propyL 77-butyl, Ao-butyl, sec-butyL / -butyl. -CF3. -CFhCFs.or -CH2CH2F. In some embodiments, RAis optionally substituted C2-6 alkenyl. In some embodiments, RAis optionally substituted C2-6 alkynyl. In some embodiments, RAis optionally substituted Ci-6 heteroalkyl. In some embodiments, RAis optionally substituted C3-8 cycloalkyl. In some embodiments, RAisoptionally substituted C3-6 cycloalkyl, e.g., cyclopropyl. In some embodiments, RAis, In some embodiments, RAis optionally substituted C2-7 heterocycloalkyl. In some embodiments, RAis optionally substituted C2-5 heterocycloalkyl. In some embodiments, RAis -OR11. In some embodiments, RAis -O-C1-3 alkyl. In some embodiments, RAis -OCH3, -OCH2CH3, -OCH2OMe. -OCH2CH2OH, -OC(CH3)3, or - o~v~7 OCH2CH2OCH3. In some embodiments, RAis -OCH3. In some embodiments, RAis v In some embodiments, RAis -SR11. In some embodiments, RAis -N(R12)(R11). In some embodiments, RAis -C(O)R12. In some embodiments, RAis C(O)OR12. In some embodiments, RAis -OC(O)R12. In some embodiments, RAis -OC(O)N(R12)(Rn). In some embodiments, RAis -C(O)N(R12)(Rn). In some embodiments, RAis -N(R12)C(O)R12. In some embodiments, RAis - N(R12)C(O)OR12. In some embodiments, RAis -N(R12)C(O)N(R12)(Rn). In some embodiments. RAis -N(R12)2S(O)2(R12). In some embodiments, RAis -S(O)R12. In some embodiments, RAis - S(O)2R12. In some embodiments, RAis -S(O)2N(R12)(Rn).

[0102] In some embodiments of a compound of Formula (IV a), (IVa-1), and (IVa-2), R11is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C1-4 alkylene-Cs-s cycloalkyl, optionally substituted -C1.4 alkylene-C2-7 heterocycloalkyd, optionally substituted -C1-4 alkylene-phenyl, or optionally substituted -C1-4 alkylene-heteroaryl. In some embodiments. R11is hydrogen. In some embodiments, R11is optionally substituted C1-6 alkyl. In some embodiments, R11is optionally substituted C1-3 alkyl. In some embodiments, R11is methyl, ethyl, propyl, wo-propyl, w-butyl, zso-butyl, sec-butyl, / -butyl, -CF3, -CH2CF3.or -CH2CH2F. In some embodiments, R11is optionally substituted C2-6 alkenyl. In some embodiments, R11is optionally substituted C2-6 alkynyl. In some embodiments, R11is optionally substituted C1-6 heteroalkyl. In some embodiments, R11is optionally substituted C3-8 cycloalkyl. In some embodiments, R11is optionally substituted C2-7 heterocycloalkyl. In some embodiments, R11is optionally substituted phenyl. In some embodiments, R11is optionally substituted heteroaryl. In some embodiments, R11is optionally substituted -C1-4 alkylene-C3-8 cycloalkyl. In some embodiments, R11is optionally substituted -C1-4 alkylene-C2-7 heterocycloalkyd. In some embodiments, R11isoptionally substituted -C alkylene-phenyl. In some embodiments, R11is optionally substituted -C alkylene-heteroaryl.

[0103] In some embodiments of a compound of Formula (IV a), (IVa-1), and (IVa-2), each of R12is independently selected from hydrogen, halogen, -OH, -NO2, CN, CM alkyl, C aminoalkyl, CM hydroxyalkyl, CM haloalkyl. CM heteroalkyl. C3-6 carbocycle, and 3- to 6- membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, CN, CM alkyl. CM alkoxy, and CM haloalkyl. In some embodiments of a compound of Formula (IV a), (IVa-1), and (IVa-2), each of R12is independently selected from hydrogen, -NO2, CN, CM alkyl. CM aminoalkyl. CM hydroxyalkyl. C haloalkyl, CM heteroalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo. amino. -NO2, CN, CM alkyl, CM alkoxy, and CM haloalkyl. In some embodiments, R12is hydrogen. In some embodiments, R12is halogen. In some embodiments, R12is -OH. In some embodiments, R12is -NO2. In some embodiments, R12is CN. In some embodiments, R12is CM alkyl. In some embodiments, R12is CM aminoalkyl. In some embodiments, R12is CM hydroxy alkyl. In some embodiments, R12is CM haloalkyl. In some embodiments, R12is CM heteroalkyl. In some embodiments, R12is C3-6 carbocycle. In some embodiments, R12is and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, CN, CM alkyl, CM alkoxy, and CM haloalkyl. In some embodiments, the one or more substituents is halogen. In some embodiments, the one or more substituents is -OH. In some embodiments, the one or more substituents is oxo. In some embodiments, the one or more substituents is amino. In some embodiments, the one or more substituents is -NO2. In some embodiments, the one or more substituents is CN. In some embodiments, the one or more substituents is CM alkyl. In some embodiments, the one or more substituents is CM alkoxy. In some embodiments, the one or more substituents is CM haloalkyl.

[0104] In some embodiments of a compound of Formula (IV a), (IVa-1), and (IVa-2), RB1is optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl. In some embodiments. RB1is optionally substituted C3-8 cycloalkyl. In some embodiments, RB1is optionally substituted C2-9 heterocycloalkyl. In some embodiments, RB1is optionally substituted 5-6 membered heterocycloalkyl. In some embodiments, RB1is optionally substituted naphthyl. In some embodiments, RB1is optionallysubstituted phenyl. In some embodiments, RB1is optionally substituted monocyclic heteroaryl. In some embodiments, RB1is optionally substituted bicyclic heteroaryl.

[0105] In some embodiments of a compound of Formula (IV a), (IVa-1), and (IVa-2), RY1is hydrogen, halo, -CN, -NO2, -OR11, -SR11, -N(R12)(Rn), optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted O)N(R12)(RU),C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, and optionally substituted bicyclic heteroaryl. In some embodiments, RY1is hydrogen. In some embodiments, RY1is halo. In some embodiments, RY1is -CN. In some embodiments, RY1is -NO2. In some embodiments, RY1is -OR11. In some embodiments. RY1is -SR11. In some embodiments. RY1is -N(R12)(Rn). In some embodiments, RY1is optionally substituted C1-6 alkyl. In some embodiments, RY1is optionally substituted C1-6 heteroalkyl. In some embodiments, RY1is optionally substituted C2-6 alkenyl. In some embodiments, R1is optionally substituted C2-6 alkynyl. In some embodiments, RY1is -OR11. In some embodiments. RY1is -SR11. In some embodiments. RY1is -N(R12)(Rn). In some embodiments, RY1is -C(O)R12. In some embodiments, RY1is -C(O)OR12. In some embodiments, R is -OC(O)R12. In some embodiments, R ‘1is -OC(O)N(R12)(Rn). In some embodiments, RY1is -C(O)N(R12)(Rn). In some embodiments, RY1is -N(R12)C(O)R12. In some embodiments, RY1is -N(R12)C(O)OR12. In some embodiments, RY1is -N(R12)C(O)N(R12)(R11). In some embodiments. RY1is -N(R12)S(O)2(R12). In some embodiments, RY1is -S(O)R12. In some embodiments, R1 1is -S(O)2R12. In some embodiments, R^1is -S(O)2N(R12)(Rn). In some embodiments, R'1 1is optionally substituted C3-8 cycloalkyl. In some embodiments, RY1is optionally substituted C2-9 heterocycloalkyl. In some embodiments, RY1is optionally substituted naphthyl. In some embodiments. RY1is optionally substituted phenyl. In some embodiments, RY1is optionally substituted monocyclic heteroaryl. In some embodiments, RY 1is optionally substituted bicyclic heteroaryl.

[0106] In some embodiments of a compound of Formula (IV a), (IVa-1), and (IVa-2), RY2is hydrogen, halo, -CN, -NO2, -OR11, -SR11, -N(R12)(Rn), optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, -OR11, -SR11, -N(R12)(Rn), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)(RU), -C(O)N(R12)(Rn), -N(R12)C(O)R12-N(R12)C(O)OR12, -N(R12)C(O)N(R12)(RU), - N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)(Rn), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionallysubstituted phenyl, optionally substituted monocyclic heteroaryl, and optionally substituted bicyclic heteroaryl. In some embodiments, RY2is hydrogen. In some embodiments, RY2is halo. In some embodiments, RY2is -CN. In some embodiments, RY2is -NO2. In some embodiments, RY2is -OR11. In some embodiments, RY2is -SR11. In some embodiments, RY2is -N(R12)(Rn). In some embodiments, RY2is optionally substituted Ci-6 alkyl. In some embodiments, RY2is optionally substituted C 1-6 heteroalkyl. In some embodiments, RY2is optionally substituted C2-6 alkenyl. In some embodiments, RY2is optionally substituted C2-6 alkynyl. In some embodiments, RY2is -OR11. In some embodiments, RY2is -SR11. In some embodiments, RY2is -N(R12)(Rn). In some embodiments, RY2is -C(O)R12. In some embodiments, R2is -C(O)OR12. In some embodiments, RY 2is -OC(O)R12. In some embodiments, RY2is -OC(O)N(R12)(Rn). In some embodiments, R12is -C(O)N(R12)(Rn). In some embodiments, RY2is -N(R12)C(O)R12. In some embodiments, RY2is -N(R12)C(O)OR12. In some embodiments, RY2is -N(R12)C(O)N(R12)(Rn). In some embodiments. RY2is -N(R12)S(O)2(R12). In some embodiments, RY2is -S(O)R12. In some embodiments, RY2is -S(O)2R12. In some embodiments, RY2is -S(O)2N(R12)(Rn). In some embodiments, RV2IS optionally substituted C3-8 cycloalkyl. In some embodiments, RV2is optionally substituted C2-9 heterocycloalkyl. In some embodiments, RY2is optionally substituted naphthyl. In some embodiments. RY2is optionally substituted phenyl. In some embodiments, RY2is optionally substituted monocyclic heteroaryl. In some embodiments. RY2is optionally substituted bicyclic heteroaryl.

[0107] In some embodiments of a compound of Formula (IV a), (IVa-1), and (IVa-2), RY3is hydrogen, halo, -CN, -NO2, -OR11, -SR11, -N(R12)(Rn), optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, -OR11, -SR11, -N(R12)(Rn), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)(Rn), -C(O)N(R12)(Rn), -N(R12)C(O)R12-N(R12)C(O)OR12, -N(R12)C(O)N(R12)(R11), - N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)(Rn), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, and optionally substituted bicyclic heteroaryl. In some embodiments, RY3is hydrogen. In some embodiments, RY3is halo. In some embodiments, RY’ is -CN. In some embodiments, RY3is -NO2. In some embodiments, RY3is -OR11. In some embodiments, RY 3is -SR11. In some embodiments, RY3is -N(R12)(Rn). In some embodiments, RY3is optionally substituted C1-6 alkyl. In some embodiments, RY3is optionally substituted C 1-6 heteroalkyl. In some embodiments, RY3is optionally substituted C2-6 alkenyl. In some embodiments, R33is optionally substituted C2-6 alky nyl. In some embodiments, RY' is -OR11. In some embodiments, RY3is -SR11. In some embodiments, RY' is -N(R12)(Rn). In some embodiments, RY3is -C(O)R12. In some embodiments, RY 3is -C(O)OR12. In someembodiments, In some embodiments, R^3is -OC(O)N(R12)(Rn). In some embodiments, )(Rn). In some embodiments, RY3is -N(R12)C(O)R12. In some embodiments,)OR12. In some embodiments, RY3is -N(R12)C(O)N(R12)(Rn). In some embodiments, RY3is -N(R12)S(O)2(R12). In some embodiments, RY3is -S(O)R12. In some embodiments, RY3is -S(O)2R12. In some embodiments, RY3is -S(O)2N(R12)(Rn). In some embodiments, R'13is optionally substituted C3-8 cycloalkyl. In some embodiments, R13is optionally substituted C2-9 heterocycloalkyl. In some embodiments, RY3is optionally substituted naphthyl. In some embodiments. RY3is optionally substituted phenyl. In some embodiments, RY3is optionally substituted monocyclic heteroaryl. In some embodiments. RY3is optionally substituted bicyclic heteroaryl.

[0108] In some embodiments of a compound of Formula (IV a), (IVa-1), and (IVa-2), RY4is hydrogen, halo, -CN. -NO2, -OR11, -SR11. -N(R12)(Rn), optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, -OR11, -SR11, -N(R12)(Rn), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)(RU), -C(O)N(R12)(Rn), -N(R12)C(O)R12-N(R12)C(O)OR12, -N(R12)C(O)N(R12)(RU), - N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)(RU), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, and optionally substituted bicyclic heteroaryl. In some embodiments, RY4is hydrogen. In some embodiments, RY4is halo. In some embodiments, RY4is -CN. In some embodiments, RY4is -NO2. In some embodiments, RY4is -OR11. In some embodiments, RY4is -SR11. In some embodiments, RY4is -N(R12)(Rn). In some embodiments, RY4is optionally substituted Ci-6 alkyl. In some embodiments, RY4is optionally substituted C 1-6 heteroalkyl. In some embodiments, RY4is optionally substituted C2-6 alkenyl. In some embodiments, R4IS optionally substituted C2-6 alkynyl. In some embodiments, RY4is -OR11. In some embodiments, RY4is -SR11. In some embodiments, RY4is -N(R12)(Rn). In some embodiments, RY4is -C(O)R12. In some embodiments, RYIis -C(O)OR12. In some embodiments, In some embodiments, R3 4IS -OC(O)N(R12)(Rn). In some embodiments, )(Rn). In some embodiments, RY4is -N(R12)C(O)R12. In some embodiments,)OR12. In some embodiments, RY4is -N(R12)C(O)N(R12)(Rn). In some embodiments, RY4is -N(R12)S(O)2(R12). In some embodiments, RY4is -S(O)R12. In some embodiments, RY4is -S(O)2R12. In some embodiments, RY4is -S(O)2N(R12)(Rn). In some embodiments, R4is optionally substituted C3-8 cycloalkyl. In some embodiments, R1 4IS optionally substituted C2-9 heterocycloalkyl. In some embodiments, RY4is optionally substituted naphthyl. In some embodiments. RY4is optionally substituted phenyl. In some embodiments.RY4is optionally substituted monocyclic heteroaryl. In some embodiments, R'4IS optionally substituted bicyclic heteroaryl.

[0109] In some embodiments of a compound of Formula (IV a), (IVa-1), and (IVa-2), RY1and RY2are taken together with the carbons to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl. In some embodiments of a compound of Formula (IV a), (IVa-1), and (IVa-2), RY3and RY4are taken together with the carbons to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl.

[0110] In some embodiments of a compound of Formula (IV a). (IVa-1), and (IVa-2) , m is1, 2, 3, or 4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0111] In some embodiments of a compound of Formula (IV a), (IVa-1), and (IVa-2) p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.

[0112] In some embodiments of a compound of Formula (IVa-2), Y1is N or CRY1; Y2is N or CRY2; Y3is CR^3; Y4is CR'4; each of RY1, RY2, R^3, and RY4is independently hydrogen orCi-Ce alkyl; R1is hydrogen or Ci-Ce alkyeach RAis independently OH, C1-6 alkoxyl(e.g., -OCH3), C 1-6 alky l, C 1-6 haloalkyl, or C3-C6 cycloalkyl (e.g , cyclopropyl); and RB1is 5 membered heteroaryl optionally substituted with one or more substituents selected from C1-3 haloalkylsome embodiments, RB1is substituted with 1 or 2 substituents selected fromC1-3 haloalkyl and C1-3 alkyl. In some embodiments, each RAis independently OH. C1-3 alkyl, Ci- 3 alkoxyl (e.g. , -OCH3), C 1-3 haloalkyl, or Cs-Ce cycloalkyl (e.g., cyclopropyl). In some embodiments, each RAis independently C1-3 alkoxyl (e.g., -OCH3) or C3-C6 cycloalkyl (e.g, cyclopropyl). In some embodiments, each RAis independently -OCH3, C1-3 alkyl, C1-3 haloalkyl,or cyclopropyl. In some embodiments, each RAis independently C1.3 alkoxyl, C1.3 alkyl, C1-3 haloalkyl, or cyclopropyl. In some embodiments, -OCH3 is -OCD3.

[0113] In one aspect, described herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) a compound having the structure of Formula (VI), or a pharmaceutically acceptable salt thereof:wherein, ring C is phenyl or a 5 membered heteroaryl, wherein each of the phenyl or heteroaryl is optionally substituted; ring D is an aromatic, saturated or partially saturated 6 membered carbocycle or heterocycle, wherein each of the carbocycle or heterocycle is optionally substituted; each of R8and R9is independently selected from hydrogen, halo. -CN, optionally substituted Ci- 6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl; or R8and R9taken together form an oxo; or R8and R9taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl; ring A is phenyl, naphthyl, monocyclic heteroaryl, bicyclic heteroaryl, cycloalkyl, or heterocycloalkyl; each of RAis independently selected from halogen, -NO2, oxo, -CN, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR11, -SR11, -N(R12)(Rn), -C(O)R12, -C(O)OR12, -OC(O)R12, - OC(O)N(R12)(Rn), -C(O)N(R12)(Rn), -N(R12)C(O)R12-N(R12)C(O)OR12, - N(R12)C(O)N(R12)(Rn), -N(R12)2S(O)2(R12), -S(O)R12, -S(O)2R12, and -S(O)2N(R12)(Rn);R11is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C1-4 alky lene-C'3-8 cycloalkyl, optionallysubstituted -C1.4 alky lene-C2-7 heterocycloalkyl, optionally substituted -Ci-4 alkylene-phenyl, or optionally substituted -C1-4 alk lene-heteroaryl: each of R12is independently selected from hydrogen, halogen, -OH, -NO2, -CN, C1-6 alkyl, C1-6 aminoalkyl, Ci-ghydroxyalkyl, Ci-ehaloalkyl, and C3-6 carbocycle, 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, -CN, C1-6 alkyl, Ci-6 alkoxy, and Ci-g haloalkyl;RRis hydrogen, halo, -CN, -NO2, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, -OR11, -SR11. -N(R12)(Rn), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)(RU), -C(O)N(R12)(RH), - N(R12)C(O)R12-N(R12)C(O)OR12, -N(R12)C(O)N(R12)(RU), -N(R12)S(O)2(R12), -S(O)R12, - S(O)2R12, -S(O)2N(R12)(RH), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; or m is 0, 1, 2, 3, or 4; and p is 0 or 1;(b) an additional agent, wherein the combined amount of the compound of Formula (IV). or a pharmaceutically acceptable salt thereof and the additional agent is therapeutically effective for treating the cancer.

[0114] Non-limiting examples of compounds that can be used in the method described herein are compounds presented in Table 1, and pharmaceutically acceptable salts thereof.Table 1. Exemplary Compounds of the Disclosure

[0115] Table 2 presents corresponding biological data for USP1 IC50 (nM) and MDA-MB- 436 IC50 (nM) for the compounds presented in Table 1.IC50 (nM): 0<A<50; 50<B<l,000; 1,OOO<C<10,000

[0116] Therefore, in one aspect, described herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) an amount of one or more of compounds 1-32 disclosed herein or a pharmaceutically acceptable salt thereof; and(b) an amount of an additional agent.

[0117] In one aspect, described herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) an amount of a compound of Formula (IVa-2)pharmaceutically acceptable salt thereof; and(b) an amount of an additional agent. In some embodiments, the compound of Formula (IVa-2) is one of the compounds listed in Table 1.

[0118] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) an amount(Compound 1) or a pharmaceutically acceptable salt thereof; and(b) an amount of an additional agent.

[0119] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof the method comprising administering to the subject:(a) an amount(Compound 3) or a pharmaceutically acceptable salt thereof; and(b) an amount of an additional agent.

[0120] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) an amount(Compound 4) or a pharmaceutically acceptable salt thereof: and(b) an amount of an additional agent.

[0121] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) an amount(Compound 5) or a pharmaceutically acceptable salt thereof and(b) an amount of an additional agent.

[0122] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof the method comprising administering to the subject:(a) an amount(Compound 6) or a pharmaceutically acceptable salt thereof and(b) an amount of an additional agent.

[0123] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof the method comprising administering to the subject:(a) an amount(Compound 7) or a pharmaceutically acceptable salt thereof and(b) an amount of an additional agent.

[0124] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof the method comprising administering to the subject:(a) an amount(Compound 8) or a pharmaceutically acceptable salt thereof and(b) an amount of an additional agent.

[0125] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof the method comprising administering to the subject:(a) an amount(Compound 9) or a pharmaceutically acceptable salt thereof: and(b) an amount of an additional agent.

[0126] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(Compound 10) or a pharmaceutically acceptable salt thereof; and(b) an amount of an additional agent.

[0127] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) an amount(Compound 11) or a pharmaceutically acceptable salt thereof; and(b) an amount of an additional agent.

[0128] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(Compound 15) or a pharmaceutically acceptable salt thereof; and(b) an amount of an additional agent.

[0129] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(Compound 17) or a pharmaceutically acceptable salt thereof; and(b) an amount of an additional agent.

[0130] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) an amount(Compound 18) or a pharmaceutically acceptable salt thereof; and(b) an amount of an additional agent.

[0131] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) an amount(Compound 24) or a pharmaceutically acceptable salt thereof; and(b) an amount of an additional agent.

[0132] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof the method comprising administering to the subject:(Compound 25) or a pharmaceutically acceptable salt thereof; and(b) an amount of an additional agent.

[0133] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) an amount(Compound 27) or a pharmaceutically acceptable salt thereof: and(b) an amount of an additional agent.

[0134] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof the method comprising administering to the subject:(a) an amount(Compound 28) or a pharmaceutically acceptable salt thereof: and(b) an amount of an additional agent.

[0135] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) an amount o(Compound 30) or a pharmaceutically acceptable salt thereof: and(b) an amount of an additional agent.

[0136] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) an amount(Compound 31) or a pharmaceutically acceptable salt thereof; and(b) an amount of an additional agent.

[0137] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof the method comprising administering to the subject:(a) an amount(Compound 32) or a pharmaceutically acceptable salt thereof; and(b) an amount of an additional agent.

[0138] In some embodiments, the combined amount of a compound of Formula (IV a) or Formula (IVa-2) or the pharmaceutically acceptable salt thereof and the additional agent are therapeutically effective.

[0139] In one aspect, described herein is use of a compound of Formula (IV a) or Formula (IVa-2) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein the medicament is formulated for being administered in combination with an additional agent.

[0140] In one aspect, described herein is use of a compound of Formula (IV a) or Formula (IVa-2) or a pharmaceutically acceptable salt thereof and an additional agent in the manufacture of a medicament for treating cancer.

[0141] In one aspect, described herein is use of a compound of Formula (IV a) or Formula (IVa-2) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein the medicament is formulated for being administered in combination with an additional agent.

[0142] In one aspect, described herein is use of a compound of Formula (IV a) or Formula (IVa-2) or a pharmaceutically acceptable salt thereof and an additional agent in the manufacture of a medicament for treating cancer.

[0143] In some embodiments of the method disclosed herein, the cancer is leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL). Hodgkin lymphoma (HL), or multiple myeloma (MM).

[0144] In some embodiments, the cancer is a carcinoma, squamous carcinoma, adenocarcinoma, sarcomata, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, primary peritoneal cancer, colon cancer, colorectal cancer, squamous cell carcinoma of the anogenital region, melanoma, renal cell carcinoma, lung cancer, non-small celllung cancer, squamous cell carcinoma of the lung, stomach cancer, bladder cancer, gall bladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, glioblastoma, glioma, squamous cell carcinoma of the head and neck, prostate cancer, pancreatic cancer, mesothelioma, sarcoma, hematological cancer, leukemia, lymphoma, neuroma, and combinations thereof. In some embodiments, a cancer to be treated by the methods of the present disclosure include, for example, carcinoma, squamous carcinoma (for example, cervical canal, eyelid, tunica conjunctiva, vagina, lung, oral cavity, skin, urinary bladder, tongue, larynx, and gullet), and adenocarcinoma (for example, prostate, small intestine, endometrium, cervical canal, large intestine, lung, pancreas, gullet, rectum, uterus, stomach, mammary gland, and ovary). In some embodiments, a cancer to be treated by the methods of the present disclosure further include sarcomata (for example, myogenic sarcoma), leukosis, neuroma, melanoma, and lymphoma. In some embodiments, a cancer to be treated by the methods of the present disclosure is breast cancer. In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is triple negative breast cancer (TNBC). In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is ovarian cancer. In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is colorectal cancer. In some embodiments, the cancer is a homologous- recombination deficient cancer. In some embodiments, the cancer comprises cancer cells with a mutation in a gene encoding p53.

[0145] In some embodiments, a patient or population of patients to be treated with a pharmaceutical composition of the present disclosure have a solid tumor. In some embodiments, a solid tumor is a melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gall bladder cancer, laryngeal cancer, liver cancer, thyroid cancer, stomach cancer, salivary gland cancer, prostate cancer, pancreatic cancer, or Merkel cell carcinoma. In some embodiments, a patient or population of patients to be treated with a pharmaceutical composition of the present disclosure have a hematological cancer. In some embodiments, the patient has a hematological cancer such as Diffuse large B cell lymphoma (“DLBCL”), Hodgkin’s lymphoma (“HL”), Non-Hodgkin’s lymphoma (“NHL”), Follicular lymphoma (“FL”), acute myeloid leukemia (“AML”), or Multiple myeloma (“MM”). In some embodiments, a patient or population of patients to be treated having the cancer selected from the group consisting of ovarian cancer, lung cancer and melanoma.

[0146] Specific examples of cancers that can be prevented and / or treated in accordance with present disclosure include, but are not limited to, the following: renal cancer, kidney cancer, glioblastoma multiforme, metastatic breast cancer; breast carcinoma; breast sarcoma; neurofibroma; neurofibromatosis; pediatric tumors; neuroblastoma; malignant melanoma;carcinomas of the epidermis; leukemias such as but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, ery throleukemia leukemias and myelodysplastic syndrome, chronic leukemias such as but not limited to, chronic myelocy tic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomas such as but not limited to Hodgkin’s disease, non-Hodgkin’s disease; multiple myelomas such as but not limited to smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma and extramedullary plasmacytoma; Waldenstrom’s macroglobulinemia; monoclonal gammopathy of undetermined significance; benign monoclonal gammopathy; heavy chain disease; bone cancer and connective tissue sarcomas such as but not limited to bone sarcoma, myeloma bone disease, multiple myeloma, cholesteatoma-induced bone osteosarcoma, Paget's disease of bone, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi’s sarcoma, leiomyosarcoma, liposarcoma, lymphangio sarcoma, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; brain tumors such as but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; breast cancer including but not limited to adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, Paget's disease (including juvenile Paget’s disease) and inflammatory breast cancer; adrenal cancer such as but not limited to pheochromocytom and adrenocortical carcinoma; thyroid cancer such as but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; pancreatic cancer such as but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; pituitary cancers such as but limited to Cushing’s disease, prolactin-secreting tumor, acromegaly, and diabetes insipius; eye cancers such as but not limited to ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; vaginal cancers such as squamous cell carcinoma, adenocarcinoma, and melanoma; vulvar cancer such as squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget’s disease; cervical cancers such as but not limited to. squamous cell carcinoma, and adenocarcinoma; uterine cancers such as but not limited to endometrial carcinoma and uterine sarcoma; ovarian cancers such as but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; cervical carcinoma; esophageal cancers such as but not limited to, squamous cancer, adenocarcinoma, adenoid cycticcarcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; stomach cancers such as but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma. fibrosarcoma, and carcinosarcoma; colon cancers; colorectal cancer. KRAS mutated colorectal cancer; colon carcinoma; rectal cancers; liver cancers such as but not limited to hepatocellular carcinoma and hepatoblastoma, gallbladder cancers such as adenocarcinoma; cholangiocarcinomas such as but not limited to pappillary, nodular, and diffuse; lung cancers such as KRAS-mutated non-small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma and small-cell lung cancer; lung carcinoma; testicular cancers such as but not limited to germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk-sac tumor), prostate cancers such as but not limited to, androgen-independent prostate cancer, androgen-dependent prostate cancer, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; penal cancers; oral cancers such as but not limited to squamous cell carcinoma; basal cancers; salivary7gland cancers such as but not limited to adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; pharynx cancers such as but not limited to squamous cell cancer, and verrucous; skin cancers such as but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acrallentiginous melanoma; kidney cancers such as but not limited to renal cell cancer, adenocarcinoma, hypernephroma, fibrosarcoma, transitional cell cancer (renal pelvis and / or uterer); renal carcinoma; Wilms' tumor; bladder cancers such as but not limited to transitional cell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma. In addition, cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinomas.

[0147] In some embodiments, the cancer is lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, and breast cancer. In some embodiments, the cancer is ovarian or breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is breast cancer.

[0148] In some embodiments, the cancer can comprise cancer cells with elevated levels of RAD 18 mRNA expression. In some embodiments, elevated levels of RAD 18 are elevated levels of RAD 18 protein. In some embodiments, RAD 18 levels can be detected usingquantitative methods like microarray, RNA-Seq, or reverse transcriptase polymerase chain reaction (RT-PCR). In some embodiments, the levels of RAD 18 in a cancer cell can be detected prior to administration of the compounds described herein. In some embodiments, RAD 18 levels can be detected in a cancer sample obtained from a subject. In some embodiments, if a subject has elevated levels of RAD 18, the subject can be treated with the compounds described herein. In some embodiments, elevated levels of RAD 18 in cancer cells indicate that a subject administered the compounds or pharmaceutical compositions described herein is responsive to treatment using the compounds or pharmaceutical compositions described herein. In some embodiments, the compounds described herein are not administered to a subject with elevated levels of RAD 18.

[0149] In some embodiments, the cancer is a DNA damage repair pathway deficient cancer. In some embodiments, the cancer is a PARP inhibitor resistant or refractory' BRCA1 or BRCA2- mutant cancer. In some embodiments, the cancer comprises cells with elevated levels of RAD 18, where the elevated levels of RAD 18 are at least as high as the RAD 18 mRNA and / or protein levels in ES2 cells or HEP3B217 cells.

[0150] In some embodiments, the cancer is a BRCA1 mutant cancer and / or a BRCA2 mutant cancer. In some embodiments, the cancer is a BRCA1 or BRCA2 wildtype cancer. In some embodiments, the cancer is a BRC Al -deficient cancer. In some embodiments, the cancer is a BRCA2-deficient cancer. In some embodiments, the cancer that comprises cancer cells with a mutation in a gene that encodes BRC Al and / or BRCA2. In some embodiments, the cancer is a BRC Al mutant cancer and BRCA2 deficient cancer. In some embodiments, the cancer is a BRCA1 deficient cancer and BRCA2 mutant cancer. In some embodiments, the cancer comprises cells with elevated levels of RAD 18, where the elevated levels of RAD 18 are at least as high as the RAD 18 mRNA and / or protein levels in ES2 cells or HEP3B217 cells.

[0151] In some embodiments, the additional agent is a DNA Damage Response Pathway (DDR) inhibitor, an mTOR inhibitor, an immune checkpoint inhibitor, a cell cycle inhibitor, a radiopharmaceutical agent, an anti-angiogenic agent, an antitubulin agent, a DNA synthesis inhibitor, a DNA alkylating agent, a topoisomerase inhibitor, a chemotherapeutic agent, or any combination thereof.

[0152] In some embodiments, the additional agent is a DDR inhibitor. In some embodiments, the DDR pathway inhibitor is a PARP inhibitor, an ATM inhibitor, an ATR inhibitor, a WEE1 inhibitor, an APE1 inhibitor, a CHK1 inhibitor, or any combination thereof.

[0153] In some embodiments, the DDR pathway inhibitor is a PARP inhibitor. The Poly (ADP-ribose) polymerase (PARP) family of enzymes plays roles in DNA repair and genome integrity. PARP is critical for single stranded break repair and base excision repair pathways.PARP is critical for the recruitment of DNA repair proteins to the damage sites. PARP inhibitors prevent the repair of DNA single-stranded breaks and promote the conversion of single-stranded breaks to double-stranded breaks, which creates synthetic lethality7in cancer cells that lack proficient double-stranded break mechanisms such as homologous recombination, and such cancer cells would depend on other mechanisms including USP1 for DNA repair. Therefore, the combination of a USP1 inhibitor described herein with a PARP inhibitor provides a plausible approach for cancer treatment. In some embodiments, the PARP inhibitor is olaparib (AZD2281), veliparib (ABT-888), rucaparib, talazoparib (BMN 673), AG-14361, INO-1001 (3- aminobenzamide), A-966492, PJ34 HC1, niraparib, UPF 1069, ME0328, RK-287107, pamiparib (BGB-290), NMS-P118, E7449, picohnamide, benzamide, NU1025, iniparib (BSI-201), AZD2461, BGP-15 2HC1, XAV-939, 4-hydroxyquinazoline, NVP-TNKS656, MN 64, G007- LK, CEP-9722, CEP-8983, E7016, BYK204165, CEP-6800, DR2313, KU-0058684, L-2286, NU1064. NU1085. PUM00199, LT-673, MP-124, PF-1367338, AG014699, KU-59436, 4-HQN, fluzopanb (SHR-3162), AMXI-5001, AZD9574, CVL218, IDX-1197, senapanb (IMP4297), JPI-547, NMS-03305293, RBN-3143, RP12146, SC10914, TQB3823, or a pharmaceutically acceptable salt thereof. In some embodiments, the PARP inhibitor is olaparib (AZD2281), saruparib (AZD5305), rucaparib, niraparib, talazoparib (BMN 673), or a pharmaceutically acceptable salt thereof. In some embodiments, the PARP inhibitor is olaparib (AZD2281). In some embodiments, the PARP inhibitor is rucaparib. In some embodiments, the PARP inhibitor is niraparib. In some embodiments, the PARP inhibitor is talazoparib. In some embodiments, the PARP inhibitor is a PARP 1 -selective inhibitor. Examples of PARP 1 -selective inhibitors include, but are not limited to, saruparib, AG-14361, INO-1001, NMS-P118. BYK204165, fluzoparib, AZD9574, and NMS-03305293. In some embodiments, the PARP inhibitor is saruparib.

[0154] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) an amount(Compound 1) or a pharmaceutically acceptable salt thereof; and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof the method comprising administering to the subject:(a) an amount(Compound 3) or a pharmaceutically acceptable salt thereof: and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(Compound 4) or a pharmaceutically acceptable salt thereof: and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) an amount(Compound 5) or a pharmaceutically acceptable salt thereof: and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof the method comprising administering to the subject:(a) an amount(Compound 6) or a pharmaceutically acceptable salt thereof: and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof the method comprising administering to the subject:(a) an amount(Compound 7) or a pharmaceutically acceptable salt thereof; and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof the method comprising administering to the subject:(a) an amount(Compound 8) or a pharmaceutically acceptable salt thereof and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof the method comprising administering to the subject:(a) an amount o(Compound 9) or a pharmaceutically acceptable salt thereof; and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof the method comprising administering to the subject:(Compound 10) or a pharmaceutically acceptable salt thereof: and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0163] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof the method comprising administering to the subject:(a) an amount(Compound 11) or a pharmaceutically acceptable salt thereof; and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(Compound 15) or a pharmaceutically acceptable salt thereof; and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(Compound 17) or a pharmaceutically acceptable salt thereof; and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof the method comprising administering to the subject:(a) an amount(Compound 18) or a pharmaceutically acceptable salt thereof; and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0167] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof the method comprising administering to the subject:(a) an amount(Compound 24) or a pharmaceutically acceptable salt thereof; and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) an amount(Compound 25) or a pharmaceutically acceptable salt thereof and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof the method comprising administering to the subject:(a) an amount(Compound 27) or a pharmaceutically acceptable salt thereof and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) an amount(Compound 28) or a pharmaceutically acceptable salt thereof: and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0171] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) an amount(Compound 30) or a pharmaceutically acceptable salt thereof: and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0172] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) an amount(Compound 31) or a pharmaceutically acceptable salt thereof; and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0173] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) an amount(Compound 32) or a pharmaceutically acceptable salt thereof; and(b) an amount of olaparib or saruparib or a pharmaceutically acceptable salt thereof.

[0174] In some embodiments, olaparib or saruparib or a pharmaceutically acceptable salt thereof is orally administered to a subject in need thereof before or after or concurrently with Compound 1, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound8, Compound 9, Compound 10, Compound 11, Compound 17, Compound 18, Compound 25, Compound 27, Compound 28, or Compound 30, or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is human epidermal growth factor receptor-2 (HER2)-negative BRCA-mutant (BRCAm) breast cancer, platinum-resistant high-grade serous ovarian cancer (HGSOC), platinum-sensitive HGSOC, BRCAm metastatic castration-resistant prostate cancer (mCRPC), or homologous recombination repair mutated (HRRm) advanced solid tumors.

[0175] In some embodiments, the DDR pathway inhibitor is an ATM inhibitor. ATM is a signaling kinase involved in the DNA damage response. Inhibition of this enzyme has been demonstrated to target an inactivation of homologous recombination (Hickson, I. et al. (2004) Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 64. 9152-9159). ATM plays a crucial role in detecting and repairing DNA damage caused by various factors, including radiation and chemical agents. Inhibition of ATM creates a dependency on other mechanisms including USP1 for DNA repair. Therefore, the combination of a USP1 inhibitor described herein with an ATM inhibitor provides a plausible approach for cancer treatment. In some embodiments, the ATM inhibitor is KU-55933. KU- 60019, wortmannm, torin 2, CP-466722. ETP-46464, CGK 733, AZ32. AZD1390, AZ31, AZD0156, or a pharmaceutically acceptable salt thereof.

[0176] In some embodiments, the DDR pathway inhibitor is an ATR inhibitor. ATR is a kinase involved in the DNA damage response. In response to a stalled fork, ATR activates the Fanconi Anemia (FA) pathway that coordinates DNA repair pathways allowing the reestablishment of DNA synthesis. It plays a crucial role in detecting and repairing DNA damage caused by various factors, including replication stress and genotoxic agents. Inhibition of ATR creates a dependency on other mechanisms including USP1 for DNA repair. Therefore, the combination of a USP1 inhibitor described herein with an ATR inhibitor provides a plausibleapproach for cancer treatment. In some embodiments, the ATR inhibitor is RP-3500, M-6620, berzosertib (M-6620, VX-970; VE-822), AZD-6738, AZ-20, M-4344 (VX-803), BAY-1895344, M-1774, IMP-9064, nLs-BG-129, SC-0245, BKT-300, ART-0380, ATRN-119, ATRN-212, NU-6027, or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, the DDR pathway inhibitor is a WEE1 inhibitor. Weel is a key element of the G2 cell cycle checkpoint control mediated by the ataxia-telangiectasia mutation and Rad3-related (ATR), which blocks the initiation of mitosis in response to cellular DNA damage. Inhibition of Weel abolishes the G2 checkpoint, causing cancer cells with DNA damage to undergo irregular mitosis and creates a dependency on other mechanisms including USP1 for DNA repair. Therefore, the combination of a USP1 inhibitor described herein with a Weel inhibitor provides a plausible approach for cancer treatment. In some embodiments, the WEE1 inhibitor is AZD1775 (MK1775), ZN-c3, debio 0123, IMP7068, SDR-7995, SDR-7778, NUV-569, PD0166285, PD0407824, SC-0191, DC-859 / A, bosutinib, Bos-I, or a pharmaceutically acceptable salt thereof.

[0178] In some embodiments, the DDR pathway inhibitor is an APE1 inhibitor. APE1 is a multifunctional protein involved in DNA repair and redox signaling. It plays a crucial role in base excision repair (BER) by removing damaged or mismatched DNA bases. APE1 inhibitors disrupt DNA repair and creates a dependency on other mechanisms including USP1 for DNA repair. Therefore, the combination of a USP1 inhibitor described herein with an APE1 inhibitor provides a plausible approach for cancer treatment. In some embodiments, the APE1 inhibitor is CRT0044876, AJAY-4, E3330 / APX3330, APX2009, APE1 inhibitor III, or a pharmaceutically acceptable salt thereof.

[0179] In some embodiments, the DDR pathway inhibitor is a CHK1 inhibitor. CHK1 is a serine / threonine-specific protein kinase involved in the DNA damage response. It plays a crucial role in ensuring genome integrity by coordinating cell cycle checkpoints, DNA repair, and cell survival. Inhibition of CHK1 reduces cancer cells’ ability’ to repair damaged DNA and creates a dependency on other mechanisms including USP1 for DNA repair. Therefore, the combination of a USP 1 inhibitor described herein with a CHK1 inhibitor provides a plausible approach for cancer treatment. In some embodiments, the CHK1 inhibitor is AZD7762, rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, VX-803 (M4344), GDC- 0575 (ARRY-575), SAR-020106. CCT245737. PD0166285, prexasertib (LY2606368), or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, the additional agent is an mTOR inhibitor. mTOR is a serine / threonine kinase that plays a central role in cell growth, proliferation, and metabolism. It integrates signals from nutrients, energy status, and growth factors to regulate protein synthesisand cell survival. Inhibition of mTOR affects cancer cells that rely on mTOR signaling for survival and proliferation including DNA replication and repair. Therefore, the combination of a USP1 inhibitor described herein with an mTOR inhibitor provides a plausible approach for cancer treatment. In some embodiments, the mTOR inhibitor is rapamycin or a rapalog. In some embodiments, the mTOR inhibitor is dactolisib (BEZ235), rapamycin (sirolimus), everohmus (RADOOl), AZD8055, temsirolimus (CCI- 779), PI- 103, KU-0063794, torkimb (PP242), ridaforolimus (deforolimus, MK-8669), sapanisertib (MLN0128), voxtalisib (XL765), torin 1, torin 2, omipalisib (GSK2126458), OSI-027, PF-04691502. apitolisib (GDC-0980), GSK1059615, gedatolisib (PKI-587), WYE-354, vistusertib (AZD2014). WYE-125132 (WYE- 132), PPI 21, WYE-687, WAY-600, ETP-46464, GDC-0349, XL388, GNE-477, bimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC 223), voxtalisib (XL765), zotarolimus (ABT-578), Tacrolimus (FK506), BGT226 maleate (NVP-BGT226 maleate), palomid 529 (P529). LY3023414 (samotolisib). biolimus-7, biolimus-9, azathioprine, campath 1H, chrysophanic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, the mTOR inhibitor is rapamycin (sirolimus), everolimus (RADOOl), temsirolimus (CCI- 779), ridaforolimus (deforolimus, MK-8669), zotarolimus (ABT-578, biolimus-7, biolimus-9, azathioprine, campath 1H, or a pharmaceutically acceptable salt thereof.

[0181] In some embodiments, the additional agent is an immune checkpoint inhibitor. Immune checkpoint inhibitors remove the brakes on the immune system, allowing it to recognize and attack cancer cells more effectively. Immune checkpoint inhibitors also alter the tumor microenvironment by increasing T cell infiltration and reducing immunosuppressive factors. The mechanisms of action of immune checkpoint inhibitors and USP1 inhibitors described herein are complementary, enhancing overall antitumor activity. Therefore, the combination of aUSPl inhibitor described herein with an immune checkpoint inhibitor provides a plausible approach for cancer treatment. Examples of immune checkpoint inhibitors include immuno-modulating / stimulating antibodies, e.g, an anti-PD-1 antibody, an anti- PD-L1 antibody, an anti-PD-L2 antibody, an anti-CTLA-4 antibody, an anti-TIM3 antibody, an anti -4- IBB antibody, an anti-CD73 antibody, an anti-GITR antibody, an anti-B7-H3 antibody, an anti- B7-H4 antibody, an anti-TIGIT antibody, an anti-CD80 antibody, an anti- CD86 antibody, an anti-ICOS antibody, an anti-BTLA antibody, and an anti-LAG-3 antibody. In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody. In some embodiments, the immune checkpoint inhibitor is an anti- PD-L1 antibody. In some embodiments, the immune checkpoint inhibitor is an anti-PD-L2 antibody. In some embodiments, the immune checkpoint inhibitor is an anti-CTLA-4 antibody. In some embodiments, the immune checkpoint inhibitor is nivolumab. pembrolizumab, pidilizumab, AMP-224, PF-06801591. MEDI0680, PDR001,REGN2810, SHR-12-1, TSR-042, CA-170, atezolizumab, durvalumab, KN035, BMS-936559, ipilimumab, tremelimumab, AGEN1884, AGEN2041, BMS-986016, GSK2831781, IMP321, LAG525, MGD013, or TSR-022, lambrolizumab, avelumab, MPDL3280A, MEDI- 4736, MSB 00107180, MDX-1105, arelumab, MGA271, BMS-986016. lirilumab, urelumab, PF-05082566, 1PH2101, MED1-6469, CP-870.893. Mogamuhzumab, Varhlumab. Gahximab. AMP-514. AUNP 12, Indoximod, NLG-919, INCB024360, DLBCL inhibitors, or any combination thereof. In some embodiments, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, AMP-224, PF-06801591, MEDI0680, PDR001, REGN2810, SHR-12-1, TSR-042, CA-170, atezolizumab, durvalumab. KN035, BMS-936559, ipilimumab, tremelimumab. AGEN1884, AGEN2041, BMS-986016, GSK2831781, IMP321, LAG525, MGD013, or TSR- 022, or any combination thereof.

[0182] In some embodiments, the additional agent is a cell cycle inhibitor. Cell cycle inhibitors are enzymes that regulate the cell cycle by interacting with cyclins. Cyclins activate CDKs, allowing them to phosphorylate key substrates and promote cell cycle progression. Cell cycle inhibitors trigger cell cycle arrest by preventing progression beyond the G1 phase, and induce apoptosis in cancer cells. The mechanisms of action of cell cycle inhibitors and USP1 inhibitors described herein are complementary, enhancing overall antitumor activity. Therefore, the combination of a USP1 inhibitor described herein with a cell cycle inhibitor provides a plausible approach for cancer treatment. In some embodiments, the cell cycle inhibitor is a CDK 4 / 6 inhibitor, a CDK7 inhibitor, a CDK9 inhibitor, or any combination thereof.

[0183] In some embodiments, the cell cycle inhibitor is a CDK 4 / 6 inhibitor. In some embodiments, wherein the CDK 4 / 6 inhibitor is palbociclib (PD- 0332991), alvocidib, AT7519, JNJ-7706621, PHA-793887, BMS-265246, milciclib (PHA-848125), R547, nviciclib (P276-00), MC180295, G1T38, abemaciclib, ON123300, AT7519, purvalanol A, SU9516, ribociclib (LEE011), BSJ-03-123, or a pharmaceutically acceptable salt thereof.

[0184] In some embodiments, the cell cy cle inhibitor is a CDK7 inhibitor. In some embodiments, the CDK7 inhibitor is LDC4297, THZ1, THZ2, YKL-5-124, BS-181, samuraciclib, LY3405105, PHA-793887, SNS-032 (BMS-387032), PF-562271, milciclib (PHA- 848125), or a pharmaceutically acceptable salt thereof.

[0185] In some embodiments, the cell cycle inhibitor is a CDK9 inhibitor. In some embodiments, the CDK9 inhibitor is SNS-032 (BMS-387032), LY2857785, alvocidib. or riviciclib hydrochloride (P276-00), or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, the additional agent is a radiopharmaceutical agent. Radiopharmaceutical agents create radiation-induced cytotoxicity. The emitted radiation damages the targeted cells, leading to their destruction. Radiopharmaceutical agents accumulateat specific organs or tissues based on various processes: 1) Enzymatic Interactions: Some radiopharmaceuticals interact with enzymes, leading to their accumulation in specific areas; 2) Receptor Binding: Binding to specific receptors allows radiopharmaceuticals to target particular cells or tissues; 3)Transport Processes: Radiopharmaceuticals may exploit transport mechanisms to reach their intended sites; 4) Metabolic Elimination: Damaged cells are removed from circulation through normal metabolic processes. Radiation causes DNA damage to the cancer cells and creates a dependency on mechanisms including USP1 for DNA repair. Therefore, the combination of a USP1 inhibitor described herein with a radiopharmaceutical agent provides a plausible approach for cancer treatment. In some embodiments, the radiopharmaceutical agent comprises a radioisotope. Examples of suitable radioisotopes include but are not limited to iodine (e.g.,125I,121I,131I,133I), fluorine (e.g.,18F), boron (e.g.,10B), Iron (59Fe), carbon (e.g.,nC,14C), sulfur (e.g.,35S), tritium (e.g ,3H), indium (e.g.,112In), technetium (e.g., 99mTc), Iridium (e.g..192Ir), samarium (e.g.,89Sr,153Sr), Rhenium (e.g.,186Re), Krypton (e.g.,81Kr111), Lutetium (e.g.,177Lu), Nitrogen (e.g.,13N), Oxygen (e.g.,15O), Phosphorus (e.g.,32P), Radium (e.g.,223Ra), Rubidium (e.g.,82Rb), Selenium (e.g.,75Se), and sodium (e.g.,22Na,24Na).

[0187] In some embodiments, the additional agent is an anti-angiogenic agent. Anti- angiogenic agents play a pivotal role in curtailing blood vessel growth, particularly in the context of cancer. Tumors require a blood supply to grow and release signals that stimulate angiogenesis, leading to the formation of new blood vessels. These vessels supply oxygen and nutrients to the tumor, enabling its growth, invasion, and metastasis. Anti-angiogenic agents aim to starve tumors by blocking their blood supply. The mechanisms of action of anti-angiogenic agents and USP1 inhibitors described herein are complementary, enhancing overall antitumor activity. Therefore, the combination of a USP1 inhibitor described herein with an anti- angiogenic agent provides a plausible approach for cancer treatment. In some embodiments, the anti-angiogenic agent is a VEGF inhibitor, a VEGFR inhibitor, or the combination thereof. In some embodiments, the anti-angiogenic agent is bevacizumab, cediranib. axitinib, anginex, sunitinib, sorafenib, pazopanib, vatalanib, cabozantinib, ponatinib, lenvatinib, SU6668, everolimus, lenalidomide, ramucirumab, regorafenib, thalidomide, vandetanib, ziv-aflibercept, or any combination thereof.

[0188] In some embodiments, the additional agent is an antitubulin agent. Antitubulin agents target microtubules to disrupt cellular processes. Microtubules are dynamic filaments composed of a-tubulin and P-tubulin heterodimers. They play critical roles in cell division, cell motility, and intracellular transport. Antitubulin agents interfere with microtubule dynamics, affecting cell division and viability. The mechanisms of action of antitubulin agents and USP1 inhibitors described herein are complementary, enhancing overall antitumor activity. Therefore, thecombination of a USP1 inhibitor described herein with an antitubulin agent provides a plausible approach for cancer treatment. In some embodiments, the antitubulin agent is a vinca alkaloid, colchicine, a taxane, or any combination thereof. In some embodiments, the antitubulin agent is a taxane. In some embodiments, the taxane is docetaxel, paclitaxel, accatin III, 10-deacetyltaxol. 7-xylosyl-10-deacetyltaxol, chalcomenite. 10-deacetyl-7-epitaxol, 7-epitaxol, 10- deacetylbaccatin III, 10-deacetyl chalcomenite, or a pharmaceutically acceptable salt thereof. In some embodiments, the taxane is paclitaxel.

[0189] In some embodiments, the antitubulin agent is a vinca alkaloid. In some embodiments, the vinca alkaloid is vinorelbine, vincristine, vinblastine, vinblastine N-oxide. vindesine, vinflunine, vincamine, vintafolide, deacetoxyvinzolidine, or a pharmaceutically acceptable salt thereof.

[0190] In some embodiments, the additional agent is a DNA synthesis inhibitor. DNA synthesis inhibitors interfere with the process of DNA replication, ultimately affecting cell division and viability. DNA synthesis occurs during the S phase of the cell cycle. DNA synthesis inhibitors disrupt the normal progression of DNA replication by targeting various enzymes and processes involved in DNA synthesis. The mechanisms of action of DNA synthesis inhibitors and USP1 inhibitors described herein are complementary, enhancing overall antitumor activity. Therefore, the combination of a USP1 inhibitor described herein with a DNA synthesis inhibitor provides a plausible approach for cancer treatment. In some embodiments, the DNA synthesis inhibitor is 5-fluorouracil (5-FE1), 6-mercaptopurine (6- MP), capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, pemetrexed, or a pharmaceutically acceptable salt thereof.

[0191] In some embodiments, the additional agent is a DNA alkylating agent. DNA alkylating agents directly damage DNA by adding an alkyl group to it. The alkyl group interferes with DNA replication and transcription, disrupting normal cellular processes. The alkylation creates cancer cell’s dependency on DNA repair mechanism including USP1 for DNA repair. Therefore, the combination of a USP1 inhibitor described herein with a DNA alkylating agent provides a plausible approach for cancer treatment. In some embodiments, the alkylating agent is altretamine, bendamustine, busulfan, improsulfan, piposulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, oxaliplatin, temozolomide, thiotepa, trabectedin. platinum coordination complexes, or a pharmaceutically acceptable salt thereof. In some embodiments, the alkydating agent is busulfan, improsulfan, piposulfan, or a pharmaceutically acceptable salt thereof.

[0192] In some embodiments, the additional agent is a topoisomerase inhibitor. Topoisomerase inhibitors block the action of topoisomerases. These enzymes play important roles in cellular reproduction and DNA organization, mediating the cleavage of single and double-stranded DNA to relax supercoils, untangle catenanes, and condense chromosomes in eukaryotic cells. Inhibition of topoisomerase disrupts DNA processes and causes DNA damage. Cancer cells would depend on DNA repair mechanisms including USP1 for DNA repair. Therefore, the combination of a USP1 inhibitor described herein with a topoisomerase inhibitor provides a plausible approach for cancer treatment. In some embodiments, the topoisomerase inhibitor is a topoisomerase I inhibitor, a topoisomerase II inhibitor, or the combination thereof. In some embodiments, the topoisomerase inhibitor is epipodopyyllotoxin, irinotecan, SN-38, ARC, NPC, camptothecin, topotecan, 9-nitrocamptothecin, exatecan, lurtotecan, lamellarin D9- aminocamptothecin, rubifen, gimatecan, diflomotecan, BN80927, DX-8951f, MAG-CPT, thiotepa, cyclosphosphamide, amsacrine, etoposide, etoposide phosphate, teniposide. daunorubicin, mitoxantrone, amsacrine, ellipticines, aurintricarboxylic acid, doxorubicin, HU- 331, or a pharmaceutically acceptable salt thereof.

[0193] In some embodiments, the additional agent is a chemotherapeutic agent. Chemotherapeutic agents interfere with DNA replication and transcription. They inhibit enzymes involved in DNA synthesis, leading to DNA damage and cell death. Cancer cells would depend on DNA repair mechanisms including USP1 for DNA repair. Therefore, the combination of a USPl inhibitor described herein with a chemotherapeutic agent provides a plausible approach for cancer treatment. In some embodiments, the chemotherapeutic agent is a platinum compound, a psoralen agent (e.g, methoxsalen), mitomycin C (MMC). dipoxybutane (DEB), or a pharmaceutically acceptable salt thereof. In some embodiments, the chemotherapeutic agent is a platinum compound. In some embodiments, the chemotherapeutic agent a platinum compound selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin. satraplatin. or any combination thereof.

[0194] In some embodiments, the additional agent is radiation therapy, including ultraviolet (UV) radiation and one or more forms of ionizing radiation. Radiation causes DNA damage to the cancer cells and creates a dependency on mechanisms including USP1 for DNA repair. Therefore, the combination of a USP1 inhibitor described herein with radiation therapy provides a plausible approach for cancer treatment. Ionizing radiation consists of subatomic particles or electromagnetic waves that are energetic enough to detach electrons from atoms or molecules, ionizing them. The occurrence of ionization depends on the energy of the impinging individual particles or waves. Generally, particles or photons with energies above a few electron volts (eV) are ionizing. Examples of ionizing particles are energetic alpha particles, beta particles, andneutrons. The ability of an electromagnetic wave (photons) to ionize an atom or molecule depends on its frequency. Radiation on the short-wavelength end of the electromagnetic spectrum, such as high frequency ultraviolet, x-rays, and gamma rays, is ionizing. Ionizing radiation comes from radioactive materials, x-ray tubes, and particle accelerators. In some embodiments, The one or more forms of ionizing radiation can be gamma-irradiation, X- irradiation, or beta-irradiation. In some embodiments, the ionizing radiation is X-ray therapy, cobalt-60 gamma ray irradiation, cesium-137 gamma ray irradiation, iridium- 192 gamma ray irradiation, other external beam radiotherapy, brachytherapy, or combinations thereof.

[0195] In some embodiments, the additional agent is a DNA helicase inhibitor. Helicases are molecular motors that utilize energy from nucleoside triphosphate (typically ATP) binding and hydrolysis. Their primary function is to unwind duplex DNA, remodel RNA structures, and facilitate the unidirectional metabolism of biological processes. A DNA helicase inhibitor traps DNA helicases, preventing their normal unwinding activity and reducing the chances of DNA repair. Since both DNA helicase and USP1 are involved in DNA repair and play a role in regulating DNA damage response pathways. It is plausible that combination of an USP1 inhibitor described herein with a DNA helicase inhibitor would improve cancer treatment. In some embodiments, the DNA helicase inhibitor is chosen from the group consisting of WRN, BLM, and DNA2. In some embodiments, DNA helicase inhibitors include WRN NSC 19630, WRN NSC 671145, BLM ML216, DNA2 C5, DNA2 NSC-105808, and DDX. Non-limiting examples of DNA helicase inhibitors include ML216 (N-[4-fluoro-3 -(trifluoromethyl)phenyl]- N'-[5 -(4-pyridinyl)-l,3,4-thiadiazol-2-yl]-urea; CAS 1430213-30-1). NSC 19630 (1- (propoxymethyl)-maleimide; CAS 72835-26-8), NSC 671145, NSC 105808, dibenzothiepins, derivatives thereof, analogs thereof, and combinations thereof.

[0196] In some embodiments, the additional agent is a MDM2 inhibitor. MDM2, an oncoprotein, inhibits p53 function. p53 is a tumor suppressor and transcription factor that responds to cellular stress by activating the transcription of numerous genes involved in cell cycle arrest, apoptosis, senescence, and DNA repair. MDM2 inhibits p53 activity by three mechanisms: 1) acting as an E3 ubiquitin ligase to promote p53 degradation; 2) binding to and blocking the p53 transcriptional activation domain; and 3) exporting p53 from the nucleus to the cytoplasm. All three of these mechanisms would be blocked by neutralizing the MDM2-p53 interaction, which in turn improves p53 activation. Since both p53 and USP1 are involved in DNA repair and play a role in regulating DNA damage response pathways. It is plausible that combination of an USP1 inhibitor described herein with a MDM2 inhibitor would improve cancer treatment. In some embodiments, the MDM2 inhibitor is selected from the group consisting of APG-115, SAR405838, RG7112, RG7388 (Idasanutlin), MI-773. Nutlin 3. Nutlin3a, Nutlin 3b, HDM201, Kevetrin hydrochloride, MX69, NVP-CGM097, NVP-CGM097 sulfate, Nutlin 3b, RO8994, YH239-EE, NVP-CGM097 stereoisomer, AMG 232, Triptolide, NSC59984, PRIMA-1, NSC66811, NSC207895, Serdemetan (JNJ 26854165) , R5C3, Caylin-1, Caylin-2. HLI373, NSC319726, YH239-EE, Tenovin-1, and combinations thereof.

[0197] In some embodiments, the additional agent is a cell therapy. The cell therapy is selected from among the group consisting of a tumor infiltrating lymphocytic (TIL) therapy, a transgenic TCR therapy, and a chimeric antigen receptor (CAR)-expressing cell therapy. In some embodiments, the CAR-expressing cell therapy is Carvykti (Ciltacabtagene Autoleucel), Abecma (Idecabtagene Vicleucel). Tecartus (Brexucabtagene Autoleucel), or Yescarta. In some embodiments, the TIL therapy is lifileucel (AMTAGVI).

[0198] In some embodiments, the additional agent when administered in combination with a compound of Formula (IV a), (IVa-1), or (IVa-2) or any of compounds 1-32, disclosed herein, achieves a synergistic effect. In some embodiments, the synergistic effect is exhibited by increased response rate (RR), prolonged non-progress disease, time to disease progression (TTP), slower progress of disease, reduced tumor size, prolonged survival time, higher survival rate, better efficacy, higher safety, or any combination thereof.

[0199] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein. The compounds of the present disclosure 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.

[0200] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds can exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.

[0201] As used herein, “phenyl isostere” refers to a moiety or a functional group that exhibits similar physical, biological and / or chemical properties as a phenyl group. Exemplary phenyl isosteres include, without limitation, cubane, bicyclo[l. l. l]pentane (BCP), bicyclo[2.2.1]heptane. bicyclo[2. l. I]hexane, bicyclo[2.2.2]octane, adamantane, norbomene. closo-1,2- carborane, closo-1,7- carborane, closo-1,12- carborane, and ethynyl group. In some embodiments, the phenyl isostere is cubane. In some embodiments, the phenyl isostere is an ethynyl group.

[0202] 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:

[0203] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,ljC and / or14C. 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.

[0204] Unless otherwise stated, compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, the compounds described herein may be artificially enriched in one or more particular isotopes. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes selected from deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). In some embodiments, the compounds described herein are artificially enriched in one ormore isotopes selected from2H,nC,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,3JS,34S, ■’5S,36S,35C1,37C1,79Br,81Br,ljlI, and125I. In some embodiments, the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% by molar.

[0205] In some embodiments of a compound disclosed herein, one or more of R1, R4, R4, R5, R5, R6, R6, R8, R9, RY1, RY2, RY3, RY4, R11, R12, RA, RB, RB1, R1Ca, R1Da, Ra, Rb, Rc, and / or Rdgroups comprise deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments of a compound disclosed herein, one or more 'H are replaced with one or more deuteriums in one or more of the following groups R1, R4, R4, R5, R5, R6, R6, R8, R9, R3RY2, RY3, RY4, R11, R12, RA, RB, RB1, R1Ca, R1Da, Ra, Rb, Rc, and / or Rd.

[0206] In some embodiments of a compound disclosed herein, the abundance of deuterium in each of R1, R4, R4, R5, R5, R6, R6, R8, R9, RY1, RY2, RY3, RY4, R11, R12, RA, RB, RB1, R1Ca, R1Da, Ra, Rb, Rc, and / or Rdis independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% by molar.

[0207] In some embodiments of a compound disclosed herein, one or more 'H of Ring A, Ring C, and / or Ring D are replaced with one or more deuteriums.

[0208] In certain embodiments, the compounds disclosed herein have some or all of thebH atoms replaced with2H atoms. The methods of synthesis for deuteri um-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods. Deuterium substituted compounds can be 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.

[0209] 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.

[0210] Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same ty pe 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.

[0211] The compounds described herein can 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 can 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 can also be obtained by stereoselective synthesis.

[0212] 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 can 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.

[0213] In certain embodiments, compounds or salts of the compounds can 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.

[0214] 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 can be a prodrug for another derivative or active compound.

[0215] Prodrugs are often useful because, in some situations, they can be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administrationwhereas the parent is not. Prodrugs can help enhance the cell permeability of a compound relative to the parent drug. The prodrug can also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs can 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.

[0216] 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 can be synthesized using conventional techniques.Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0217] 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).Formulation

[0218] In any embodiments of the methods disclosed above, pharmaceutical compositions comprising the compounds disclosed herein can be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent (e.g, the compounds of Formula (IV a), (IVa-1), and (IVa-2), or the additional 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; andPharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).

[0219] The compounds or pharmaceutical agent of the present disclosure can 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.Administration

[0220] Dosage, toxicity and therapeutic efficacy of any therapeutic agent can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Compounds that exhibit high therapeutic indices are advantageous. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery' system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and. thereby, reduce side effects.

[0221] The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds may be within a range of circulating concentrations that include the ED50 with little or no toxicity'. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the methods, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e.. the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to determine useful doses in humans accurately. Levels in plasma may be measured, for example, by high performance liquid chromatography. Typically, an effective amount of the compound of Formula (IV a) or a compound of Formula (IVa-2) or the additional agent, sufficient for achieving a therapeutic or prophylactic effect, may range from about 0.000001 mg per kilogram body weight per day to about 10,000 mg per kilogram body weight per day.

[0222] The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to, the severity' of the disease or disorder, previous treatments, the general health and / or age of the subject, and otherdiseases present. Moreover, treatment of a subject with a therapeutically effective amount of the therapeutic compositions described herein can include a single treatment or a series of treatments.EXAMPLES

[0223] The following examples are offered to illustrate, but not to limit the claimed disclosure. The following examples further illustrate the disclosure but, of course, should not be construed as in any way limiting its scope.

[0224] 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.

[0225] The compounds and salts of Formulas (IVa), (IVa-1), (IVa-2), and (VI) can be synthesized according to one or more illustrative schemes herein and / or techniques known in the art. Materials used herein are either commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents, which are employed for illustrative purposes. Although various steps are described and depicted in the synthesis schemes below, the steps in some cases can be performed in a different order than the order shown below; Numberings or R groups in each scheme do not necessarily correspond to that of the claims or other schemes or tables herein.Example 1. In vivo Efficacy of a USP1 inhibitor combined with a PARP inhibitor in MDA- MB-436 Human Breast CancerMethods

[0226] Cell Culture

[0227] The MDA-MB-436 tumor cell line were maintained in vitro as monolayer culture in DMEM Medium supplemented with 10% fetal bovine serum at 37°C in an atmosphere of 5% CO2 in air. The tumor cells were routinely subculture weekly by trypsin-EDTA treatment, not to exceed 4-5 passages. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation.

[0228] Method for Tumor Inoculation and Randomization

[0229] Each mouse was inoculated subcutaneously on the central right flank with MDA- MB-436 tumor cells (1 x 107) in 0.1 mL of Matrigel mixture (1: 1 ratio) for the tumor development. The treatment was started when the mean tumor size reached 154 mm3. Mice were assigned to groups such that the mean tumor volume is the same for each treatment group and time point.

[0230] Measurement Parameters

[0231] For routine monitoring, all study animals were monitored not only tumor growth but also behavior such as mobility, food and water consumption (by cage side checking only), body weight (BW), eye / hair matting and any other abnormal effect. Any mortality and / or abnormal clinical signs were recorded.

[0232] Body Weight

[0233] Body weights of all animals were measured twice a week throughout the study. Body weight change, expressed in %, were calculated using the following formula:BW change (%) = (BWoay < / BWoay o)x100, where B Woay is BW on a given day, and BWoay o is BW on Day 0 (initiation of treatment).

[0234] Tumor Measurements

[0235] The measurement of tumor size was conducted twice a week with a caliper and the tumor volume (mm3) were estimated using the formula: TV = a x b2 / 2, where a and b are long and short diameters of a tumor, respectively. The TVs were used for calculation of the tumor growth inhibition (TGI, an indicator of antitumor effectiveness) value using the formula: TGI (%) = [l-(Tn-To) / (Cn-Co)]x100%., only over the dosing period (dosing days 0 to days n), where: Tn- is the avg tumor volume at the respective day "‘n” after dosing throughout treatment period; To - is the avg tumor volume in the treatment group at day 0 before treatment (immediately before); Cn- avg tumor volume in the control group at the respective day “n” after dosing throughout treatment period; and Co - average tumor volume in the control group at day 0 before treatment (immediately before).

[0236] Sample Collection

[0237] The measurement of tumor size will be conducted twice a week with a caliper and the tumor volume (mm3) will be estimated using the formula: TV = a x b2 / 2, where a and b are long and short diameters of a tumor, respectively. The TVs will be used for calculation of the tumor growth inhibition (TGI, an indicator of antitumor effectiveness) value using the formula: TGI (%) = [ 1 -(Tn-To)Z(Cn-Co)]x100%, only over the dosing period (dosing days 0 to days n), where: Tn- is the avg tumor volume at the respective day “n’‘ after dosing throughout treatment period; To - is the avg tumor volume in the treatment group at day 0 before treatment(immediately before); Cn- avg tumor volume in the control group at the respective day "n" after dosing throughout treatment period; and Co - average tumor volume in the control group at day 0 before treatment (immediately before). The experiment will be terminated when the mean tumor volume exceeded 2000 mm3or severe body weight loss.

[0238] Statistical Analysis

[0239] Data Acquisition:

[0240] Protocol-required measurements and observations were recorded manually on appropriate forms, or directly on a computerized database.

[0241] Statistical Analysis

[0242] All statistical tests were conducted, and the level of significance were set at 5% or P < 0.05. The group means, standard deviation were calculated for all measurement parameters as study designed.

[0243] Synergistic effect

[0244] The synergistic effect of the two drugs was compared by the golden formula, q=E(A+B) / (EA+EB-EA EB), E(A+B) and EA, EB represent the TGI of the combination group and the TGI of the two individual treatment groups respectively. TGI. When the q value<0.85, the combination of the two drugs shows an antagonistic effect; when 0.85<q value<1.15. the combination of the two drugs shows an additive effect; when the q value>1.15. the combination of the two drugs shows a synergistic effect.Results

[0245] Mice were treated with vehicle, olaparib 50 mg / kg p.o. QD, 3mg / kg of a Compound A (of Formula IVa-2) p.o. BID combined with olaparib 50 mg / kg p.o. QD, Img / kg of Compound A p.o. BID combined with olaparib 50 mg / kg p.o. QD, 0.3mg / kg of Compound A p.o. BID combined with olaparib 50 mg / kg p.o. QD, and 6 mg / kg KSQ-4279 p.o. QD combined with olaparib 50 mg / kg p.o. QD, respectively. Mice had mean body weight loss of 5.7%, 7.6%, and 5.9% following combined treatment of 50mg / kg QD olaparib with 0.3, 1, 3 mg / kg BID of Compound A, respectively (FIG. 2). Mice following administration of 50 mg / kg QD olaparib, with TGI value of 49.3% (FIG. 1 and Table 3). olaparib at 50 mg / kg QD combined with 0.3, 1, or 3 mg / kg BID of Compound A showed significant (p < 0.05) tumor growth inhibition, with TGI values of 49.8%, 70.0%, and 91.2%, respectively, and the combination of 50 mg / kg QD olaparib with 3 mg / kg BID of Compound A showed synergistic anti-tumor effects compared with olaparib as a single agent (FIG. 1).Table 3. Antitumor Activity in Different Groups on Day 28Note:a. Mean = SEM:bvs. Vehicle, Mann-Whitney U Test.Example 2. In vivo Efficacy of a USP1 inhibitor combined with a with a PARP inhibitor in Ovarian Cancer PDX Model LD 1-2032-361588 in NU / NU MiceMethods

[0246] 1. Tumor inoculation

[0247] The tumors were sliced into 3 mm x 3 mm x 3 mm (about 45-60 mg) fragments and implanted subcutaneously in the right flank of mice (female NU / NU mice, ages 35-42 days). The test article administration and the animal numbers in each study group are shown in the following experimental design tables:Table 4. Information of groupingTable 5. Groups and treatmentsNote: regroup: mice number per group; Dosing volume: Adjust dosing volume by body weight at lOml / kg; PO.Oral administration; QD. Once a day; BIW. Twice a day, the dosing interval is about 6-8hrs.

[0248] 2. Observations

[0249] The protocol and any amendment(s) or procedures involving the care and use of animals in this study were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of Lidebiotech prior to conduct. During the study, the care and use of animals were conducted in accordance with the regulations of the Association for Assessment and Accreditation of Laboratory' Animal Care (AAALAC).

[0250] 3. Termination and samples collection

[0251] The mice were sacrificed on day 21, photo of tumors was taken and tumor weight was measured.

[0252] 4. Endpoints

[0253] 4. 1. Tumor volume was measured twice weekly in two dimensions using a caliper, and the tumor volume was expressed in mm3using the formula: V = 0.5 a x b2where a and b are the long and short diameters of the tumor, respectively.

[0254] 4.2. Tumor volume was then used for the calculation of T / C values. The T / C value is a primary indicator of TA efficacy, where T / C= TRTV / CRTVX100 % (TRTV: RTV of treated group; CRTV: RTV of vehicle control group). Relatively tumor volume was calculated according to the following formula: RTV = Vt / Vo. whereas Vt was the tumor volume on a given day, and Vo was the tumor volume on the first day of treatment initiation.

[0255] 4.3. Meanwhile, tumor volume was used for calculation of TGI of each group according to the following formula: TGI (%) = [1- (Ti-To) / (Ci-Co)] ><100%, whereas Ti is the tumor volume of treatment group on a given day, To is the tumor volume of the treatment group on the day of treatment initiation, Ci is the tumor volume of isotype control group on a given day, and Co is the tumor volume of the vehicle control group on the day of treatment initiation.

[0256] 4.4. RECIST Evaluation was calculated according to the following formula: RECISTScore = (TEND-TS) / Ts* 100 %, TEND is the tumor volume of the treatment group on the day of treatment termination, Ts is the tumor volume of the treatment group on the day of treatmentinitiation. CR (Complete regression): RECIST score = -100%, PR (Partial regression): RECIST score = -100% to -30%, SD (Stable disease): RECIST score = -30% to +20%, PD (progression of disease): RECIST score > +20%.

[0257] 4.5. The body weight was measured on the dosing days, which was used to calculate the relative change of body weight according to the following formula: RCBW (%) = (BWi - BWo) / BWox100, whereas BWi was the body weight on a given day, and BWo was the body weight on the first day of treatment initiation.

[0258] 4.6. Photo of tumor was taken and tumor weight was measured at the end of study.

[0259] 4.7. Statistical analysis. All data was described as Mean ± SEM whereas SEM =SD / SQRT (n) , in which SD is the standard deviation of the mean, n is the mice number in each group. Using one-way ANOVA for statistical analysis to compare the tumor volume of treatment groups with vehicle group. All data were analyzed with GraphPad Prism 8, while p < 0.05 meant the difference between groups reached statistical significance.Results

[0260] The objective of this study was to evaluate the efficacy of the test articles in Ovarian cancer PDX model LD 1-2032-361588 in NU / NU mice. The results were shown in FIGs. 3 A and 3B and Tables 6-7.

[0261] The mean tumor volume of vehicle control group reached 546.61 ± 43.80 mm3on day 21 after treatment initiation, meanwhile the mean tumor volumes of animals treated with Compound A, olaparib, Compound A combined with olaparib, and KSQ-4279 (lOOmg / kg) combined with olaparib (50mg / kg) were: 263.59 ± 37.76 mm3, 461.64 ± 38.29 mm3, 239.52 ± 28.34 mm3and 234.94 ± 31.90 mm3, with TGI values of 71.73%. 21.53%, 77.79% and 78.98%, respectively. Meanwhile the rates of tumor complete regression (CR) of animals treated with vehicle, Compound A, olaparib, Compound A combined with olaparib, and KSQ-4279 combined with olaparib were 0.00%, 0.00%, 0.00%, 0.00% and 0.00%, respectively; the rates of tumor partial regression (PR) were 0.00%, 0.00%. 0.00%. 0.00% and 0.00%, respectively; and the rates of stable disease (SD) were 0.00%, 37.50%, 0.00%, 25.00% and 37.50%. These results indicated that the treatment of olaparib monotherapy did not show statistically significant antitumor effect in this model compared to vehicle control group while the treatments of compound A, Compound A combined with olaparib, and KSQ-4279 combined with olaparib showed statistically significant antitumor effect in this model compared to vehicle control group (p < 0.0001). The treatment of Compound A, Compound A combined with olaparib, and KSQ- 4279 combined with olaparib showed similar antitumor effect on this model.

[0262] At the end of the study (day 21), all the tumor bearing mice were sacrificed, the tumors were removed and weighted. The mean tumor weights of vehicle group, Compound A.olaparib, Compound A combined with olaparib, and KSQ-4279 combined with olaparib group were: 0.533 ± 0.042 g, 0.271 ± 0.042 g, 0.452 ± 0.038 g, 0.218 ± 0.025 g and 0.214 ± 0.033 g. The results of tumor weight consistent well with those of tumor volumes.

[0263] In addition, none of the mice showed significant loss of body weight over the course of the treatment, indicating that all mice tolerated well to the treatments in this study assessed bybody weight changes (see FIG. 3B).Table 6. Summary of efficacy endpoints of the test articles in LD1-2032-361588 Ovarian cancer PDX model (8 mice per group)Table 7. Data analysisExample 3. In vitro AssaysColony Formation Assay

[0264] In vitro experiments were conducted using the colony formation unit (CFU) assay on various cell lines. The CFU assay involved first establishing what cell plating density enabled the development of clearly interspersed colonies on a 24-well plate when left to grow for around 14 days. Once this density had been identified, cells were plated on day 1 and on day 0, the wells were treated with DMSO or increasing concentrations of USP1 inhibitor or olaparib (30nM, lOOnM, 300nM, lOOOnM), Media was changed on day 7 containing appropriate concentrations of DMSO, USP1 inhibitor, olaparib. At or around day 14 when clearly interspersed colonies were visible in the DMSO treated wells, the cells were fixed with 100% methanol and stained using 0. 1 % crystal violet for 15 minutes at room temperature. Remove crystal violet, wash the cells with water for 4-6 times (until no background staining) and stack plates at an angle to air-dry. The cell colonies were scanned with Li-cor Odyssey and the densities of each well can be analyzed with Image Studio software. The CFU results are shown in FIG. 4, which shows that in PC3, the Prostate cancer cell line with BRCA wild type, HR proficient, USP1 inhibitor and olaparib had little to no activity as single agents up to 300nM; however, the combination of both agents led to a synergistic effect on cell grow th. Synergistic effects were shown in combination study in almost all dose (FIG. 5).Determination of IC50 values and Synergy Scores

[0265] IC50 values were calculated by fitting a two-parameter hill equation to the doseresponse measurements. Non-linear-least-squares was used to find parameter values that minimize the squared error of the model fit to measured dose response. Non-linear-least- squares estimation was performed using the minpack. Im R package, version 1.2-1. Bliss synergy scores were calculated using the synergy finder R package version 1.6.1.Example 4. A USP1 inhibitor of Formula (IVa-2) combined with paclitaxel / anti-PDl inhibits lung metastasis in 4T1 Model

[0266] Experimental Methods and Procedures

[0267] Cell Culture

[0268] 4T1 (ATCC-CRL-2539) cells were maintained in vitro as a monolayer culture inRPMI-1640 supplemented with 10% fetal bovine serum at 37°C in an atmosphere of 5% CO2 in air. The tumor cells were routinely subcultured twice weekly. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation.

[0269] Tumor Inoculation

[0270] Each mouse was be anesthetized and inoculated at the right fourth mammary fat pad with 4T1 tumor cells (0.5 x 106) in 0.1 mL PBS for tumor development. 13 animals were randomized when the average tumor volume reached 67 mm3. The test article administration and the animal numbers in each group were shown in the experimental design

[0271] Observations

[0272] All the procedures related to animal handling, care and the treatment in the study were performed according to the guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of WuXi AppTec, following the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). At the time of routine monitoring, the animals were daily checked for any effects of tumor grow th and treatments on normal behavior such as mobility', food and water consumption (by looking only), body weight gain / loss, eye / hair matting and any other abnormal effect as stated in the protocol. Death and observed clinical signs were recorded on the basis of the numbers of animals within each subset.

[0273] Tumor Measurements, Evaluation of synergism and the Endpoints

[0274] The major endpoint was to see if the tumor growth could be delayed or mice could be cured. Tumor sizes were measured three times per week in two dimensions using a caliper, and the volume were expressed in mm3using the formula: V = 0.5 a x b2where a and b are the long and short diameters of the tumor, respectively.

[0275] The tumor volume w ere then used for the calculations of TGI or Relative T / C values. TGI is calculated for each group using the formula: TGI (%) = [l-(Ti.To) / (Ci-Co)]x100; Ti is the average tumor volume of a treatment group on a given day. To is the average tumor volume of the treatment group on the first day of treatment. Ci is the average tumor volume of the vehicle control group on the same day with Ti, and Co is the average tumor volume of the vehicle group on the first day of treatment. T / C is calculated for each group using the formula: T / C (%) = Ti / Cix lOO.

[0276] Lung metastasis

[0277] In 4T1 orthotropic model, tumor lung metastases spontaneously occurred, resulting in paralysis, body weight loss of more than 20%, or death in mice. Mice with 20% body weight loss or paralysis were euthanized. The whole lung w ith metastatic nodules of each mice in the control group and treatment group (given Compound A at 15 mg / kg which was increased to 30 mg / kg on day 5 and then 50 mg / kg on day 6) was macroscopically examined as shown in FIG.6

[0278] Statistical Analysis

[0279] Summary statistics were provided for the tumor volume of each group at each time point. Statistical analysis of difference in tumor volume among the groups was conducted on the data obtained at the last day of tumor measurement before any mice in vehicle group was found to reach the humane endpoint. To compare tumor volumes of different groups at a pre-specified day, we first use Brown-Forsythe's test to check the assumption of homogeneity of variance across all groups. When the p-value of Brown-Forsythe's test is >= 0.05, we run one-way ANOVA to test overall equality of means across all groups. If the p-value of the one-w ay ANOVA is < 0.05. we further perform post hoc testing by Dunnetf s tests for comparing each treatment group with the vehicle group. All data were analyzed using GraphPad Prism 5.0. P < 0.05 was statistically significant. The survival time was analyzed by Log-rank (Mantel-Cox) test. The event of interest was the animal death. The survival time w as defined as the time from the start of dosing to death. For each group, the median survival time (MST) was calculated.

[0280] Results

[0281] Tumor lung metastasis

[0282] Groups of animals received vehicle, Compound A treatment (25 mg / kg, p.o., BID), Compound A treatment (50mg / kg. p.o., BID), Compound A treatment (100 mg / kg, p.o., BID). Paclitaxel treatment (15 mg / kg, IP, BIW). combination treatment (12.5 mg / kg of Compound A, p.o., BID combined with 15mg / kg Paclitaxel, 15mg / kg, IP, BIW), combination treatment (25 mg / kg of Compound A, p.o., BID combined with 15mg / kg Paclitaxel, 15mg / kg, IP, BIW), combination treatment (50 mg / kg of Compound A, p.o., BID combined with 15mg / kg Paclitaxel, 15mg / kg, IP, BIW), anti-PDl treatment (clone RMP1-14, 5mg / kg, IP. BIW), and combination treatment (50mg / kg of Compound A, p.o., BID combined with 5mg / kg clone RMP1-14, IP, BIW). Mice had mild body weight loss following combined treatment of Paclitaxel and anti PD1 (clone RMP1-14, from Bio X cell) with Compound A, respectively (FIG. 7). An anti-lung metastasis trend was noted in mice given 15 mg / kg BIW Paclitaxel combined with 25mg / kg or 50mg / kg of Compound A (FIG. 8). An anti-lung metastasis trend was also noted in mice given 5 mg / kg BIW anti PD1 combined with 50mg / kg BID of Compound A (FIG. 9). Accordingly, Compound A combined with paclitaxel / anti-PDl inhibits lung metastasis.Example 5. In vivo Efficacy of a USP1 inhibitor combined with a PARP inhibitor: Efficacy Study of Test Articles in MDA-MB-436 Human Breast Cancer Methods

[0283] Cell Culture

[0284] The MDA-MB-436 tumor cell line was maintained in vitro as a monolayer culture in DMEM medium supplemented with 10% fetal bovine serum at 37°C in an atmosphere of 5% CO2 in air. The tumor cells were routinely subcultured weekly by try psin-EDTA treatment. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation.

[0285] Method for Tumor Inoculation and Randomization

[0286] Each mouse was inoculated subcutaneously on the central right flank with MDA- MB-436 tumor cells (1 x 107) in 0.1 mL of DMEM medium with Matrigel mixture (l: l ratio) for tumor development. The treatment w as started when the mean tumor size reached 174 mm3. Mice were randomly assigned to the group and the mean tumor volume for each group was the same.

[0287] Measurement Parameters

[0288] For routine monitoring, all study animals were monitored not only tumor growth but also behavior such as mobility, food, and water consumption (by cage side checking only), body w eight (BW), eye / hair matting, and any other abnormal effects. Any mortality and / or abnormal clinical signs were recorded.

[0289] Body Weight

[0290] Body weights of all animals were measured t ice a week throughout the study. Body weight change, expressed in %, was calculated using the following formula:BW change (%) = (BWoay / BWoay o)x100, where B Woay is BW on a given day, and B Woay o is BW on Day 0 (initiation of treatment).

[0291] Tumor Measurements

[0292] The measurement of tumor size was conducted twice a week with a caliper and the tumor volume (mm3) was estimated using the formula: TV = 0.5 x L x W2, where L and W are the tumor length and tumor width, respectively. The TVs were used for calculation of the tumor growth inhibition (TGI, an indicator of anti -tumor effect) value using the formula: TGI (%) = [1- (Tn-To) / (Cn-Co)]x100%., only over the dosing period (dosing days 0 to days n), where: Tn- is the avg tumor volume at the respective day£'n” after dosing throughout treatment period; To - is the avg tumor volume in the treatment group at day 0 before treatment (immediately before); Cn- avg tumor volume in the control group at the respective day “n” after dosing throughout treatment period; and Co - average tumor volume in the control group at day 0 before treatment (immediately before).

[0293] Data Acquisition

[0294] Data Acquisition: Protocol-required measurements and observations w ere recorded manually on appropriate forms, or directly on a computerized database.

[0295] Statistical Analysis: The mean and standard error of tumor volumes in each group were calculated and plotted. All statistical tests were conducted, and the level of significance was presented as * P <0.05, ** P <0.01, *** P <0.001, **** p <0.0001 vs. indicated group. Statistical significance was calculated by non-parametric Mann-Whitney U-test (GraphPad Prism 9.0.0).

[0296] Mice were treated in groups for 28 days as summarized below:Results

[0297] After 28 days of treatment, animals in Group 4 (treated with Compound A at 30 mg / kg BID in combination with saruparib) had a mean body weight loss of 2.8% and animals in Group 5 (treated with Compound A at 60 mg / kg QD in combination with saruparib) had a mean body weight loss of 0.2%. Tumor growth inhibition of 50% and 64% was observed for animals in Group 2 and Group 3 (treated with single agent Compound A and saruparib), respectively (FIG. 10). Tumor growth inhibition of 103% was observed for animals in Group 6 (treated with Compound A and olaparib; FIG. 10). Animals in Groups 4 and 5 showed significant tumor growth inhibition (p < 0.0001), with TGI values of 106% and 109%, respectively. The combination of a Compound A, a USP1 inhibitor according to Formula IVa-2, as described herein (30 mg / kg BID or 60 mg / kg QD) and saruparib (0.01 mg / kg QD) achieved tumor regression and demonstrated a durable response 27 days after treatment w as stopped (FIG. 10).Example 6. In vivo Efficacy of a USP1 inhibitor combined with irinotecan: Efficacy Study of Test Articles in MDA-MB-436 Human Breast Cancer

[0298] Cell culture, tumor inoculation, randomization, measurements, data acquisition, and statistical analysis were conducted as described in Example 5. Mice were treated in groups for 28 days as summarized below:

[0299] Mice did not show a mean body weight loss following 28 days of combined treatment of 10 mg / kg QW irinotecan with 60 mg / kg QD of Compound A, a USP1 inhibitor of Formula (IVa-2). On Day 28 post-treatment start, mice following administration of single agent Compound A (group 2) or single agent irinotecan (group 3) exhibited 41% and 31% TGI, respectively (FIG. 11). Animals treated with both irinotecan and Compound A (group 4) showed significant (p < 0.0001) tumor growth inhibition, with a TGI value of 120%. The combination of 10 mg / kg QW irinotecan with 60 mg / kg QD of Compound A, USP1 inhibitor according to Formula (IVa-2), achieved tumor regression and demonstrated a durable response to the drug combination after 28 days of stopping dosing (FIG. 11).Example 7. In vivo Efficacy of a USP1 inhibitor combined with a PARP inhibitor: Efficacy Study of Test Articles in Human Ovarian Patient-derived Xenograft

[0300] Tumor fragments from stock mice were harvested and used for inoculation into mice. Each mouse was inoculated subcutaneously in the right flank with a human ovarian tumor fragment (2-3 mm in diameter) for tumor development. The randomization was done when the mean tumor size reached 159 mm3. Mice were randomly assigned to the group, and each group's mean tumor volume was the same. Measurements and data acquisition were conducted as described in Example 5.

[0301] The mean and standard error of tumor volumes in each group were calculated and plotted. To compare tumor volumes of different groups on a pre-specified day, Bartlett's test wasused to check the assumption of homogeneity of variance across all groups. When p-value of Bartlett's test was > 0.05, a one-way ANOVA was conducted to test the overall equality of means across all groups. When the p-value of the one-way ANOVA is < 0.05, post hoc testing was conducted by running Tukey's HSD (honestly significant difference) tests for all pairwise comparisons and Dunnett's tests for comparing each treatment group with the vehicle group. When the p-value of Bartlett's test was <0.05, a Kruskal-Wallis test was performed to determine the overall equality of medians among all groups. If the p-value of the Kruskal-Wallis test was <0.05, post hoc testing was conducted by running Conover's non-parametric test for all pairwise comparisons or for comparing each treatment group with the vehicle group, both with single- step p-value adjustment. All statistical tests were conducted, and the level of significance is presented as * P <0.05, ** P <0.01, *** P <0.001, **** p <0.0001 vs. indicated group.

[0302] Mice were treated in groups for 28 days as summarized below:

[0303] On Day 28 post-treatment start, mice had a mean body weight loss of 5.9% and 6.1% following 28 days of combined treatment with olaparib and Compound A (a USP1 inhibitor according to Formula IVa-2) at 12.5 mg / kg (Group 6) or 25 mg / kg (Group 7), respectively (FIG. 12). On Day 31 post-treatment start, mice following administration of single-agent Compound A in Group 2, Group 3, and Group 4 showed 29%, 44%, and 59% TGI. respectively. Mice receiving single-agent olaparib showed 83% TGI. Animals treated with olaparib and Compound A at 12.5 mg / kg BID (Group 6) or 25 mg / kg BID (Group 7) showed significant (p < 0.0001) tumor grow th inhibition, with TGI values of 108% and 108%, respectively. The combination of 50 mg / kg QD olaparib with 12.5 or 25 mg / kg BID of Compound A, a USP1 inhibitor of Formula (IVa-2), achieved tumor regression and demonstrated a durable response of drug combination after 59 days of stopping dosing (FIG. 12).Examples A > Biological Assays

[0304] Example Al : Enzymatic Assay

[0305] Human recombinant USP1 / UAF1 expressed in baculovirus infected Sf21 cells were used (R&D, E-568-050). Test compound and / or vehicle was incubated with 2 nM of USP1 / UAF 1 in modified HEPES buffer pH 8.0 for 15 minutes at RT. The reaction was initiated by addition of 500 nM of Ubiquitin Rhodamine 110 (R&D, U-555-050) for kinetic reading. Slope change of fluorescence intensity was read spectrofluorimetrically at 485 nm / 535 nm. Dose response of test compounds or reference compound ML-323 was analyzed by nonlinear regression of GraphPad prism software. Results of the assay are illustrated in Table 2.

[0306] Example A2: MDA-MB-436 Breast Cancer Cell Culture

[0307] MDA-MB-436 cells were grown in Leibovitz's L-15 medium with 10 ug / ml insulin, 16 ug / ml glutathione, 10%FBS. Cells were passaged at subconfluence after trypsinization and maintained in incubators at 37°C in a humidified atmosphere with 5% CO2.

[0308] Example A3: MDA-MB-436 Breast Cancer Cell Proliferation Assay

[0309] Cell proliferation was determined using CellTiter-Glo® Luminescent Cell Viability Assay (Promega, # G7573). MDA-MB-436 cells were seeded in 384-well plates and allowed to attach for 24 h. Compounds were added into 384-well plate by ECHO, and incubated at 37°C in a humidified atmosphere with 5% CO2. After 7 days, CellTiter-Glo was added into 384 well plates, contents were mixed on an orbital shaker at 400g for 2 min before centrifuging the plate for 2 min at 1000 rpm. After incubation at RT for 30 min, luminescence was read on envision. Results of the assay are illustrated in Table 2.EXEMPLARY EMBODIMENTS

[0310] Exemplary embodiments provided in accordance with the presently disclosed subject matter include, but are not limited to, the claims and the following embodiments:1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) a compound of Formula (IVa), or a pharmaceutically acceptable salt thereof:Formula (IVa) wherein,Y1is N or CRY1;Y2is N or CRY2;Y3is N or CRY3;Y4is N or CRY4;R1is hydrogen. -CN. optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C2-7 heterocycloalkyl; each of R4and R4is independently selected from hydrogen, halo. -CN, -OR11, -SR11, - N(R12)(RU), optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl; or R4and R4taken together form an oxo; or R4and R4taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; each of R5and R5is independently selected from hydrogen, halo, -CN, -OR11, -SR11, - N(R12)(RU), optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl; or R5and R5taken together form an oxo; or R5and R5taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; each of R6and R6is independently selected from hydrogen, halo, -CN, -OR11, -SR11, - N(R12)(R11), optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl. optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl; or R6and R6taken together form an oxo; or R6and R6taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; each of R8and R9is independently selected from hydrogen, halo, -CN, optionally substituted Ci-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl; or R8and R9taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; ring A is monocyclic heteroaryl, bicyclic heteroaryl, monocyclic heterocycloalkyl, or bicyclic heterocycloalkyl; each ofRAis independently selected from halogen, -NO2, oxo, -CN, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl,optionally substituted C2-7 heterocycloalkyl, -OR11, -SR11, -N(R12)(Rn), - C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)(R11), -C(O)N(R12)(Rn), - N(R12)C(O)R12-N(R12)C(O)OR12, -N(R12)C(O)N(R12)(RU), -N(R12)2S(O)2(R12), - S(O)R12, -S(O)2R12, and -S(O)2N(R12)(Rn);R11is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-e alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C -8 cycloalkyl. optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C1-4 alkylene-Cs-s cycloalkyl, optionally substituted -C 1-4 alkylene-C2-7 heterocycloalkyl, optionally substituted -Ci.4alkylene-phenyl, or optionally substituted -C1-4 alkyleneheteroaryl; each of R12is independently selected from hydrogen, -NO2, -CN, C1-6 alky l, Ci-6 aminoalkyl, Ci-ehydroxyalkyl, Ci-ehaloalkyl, C 1-6 heteroalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently' selected from halogen, -OH, oxo, amino, -NO2, -CN, Ci-6 alkyl, C1-6 alkoxy, and Ci-6 haloalkyl;RB1is optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; each of RY1, RY2, RYSand R4is independently selected from hydrogen, halo, -CN, - NO2, -OR11, -SR11, -N(R12)(Rn), optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6alkynyl, -OR11, -SR11, -N(R12)(Rn), -C(O)R12, -C(O)OR12, -OC(O)R12, - OC(O)N(R12)(Rn), -C(O)N(R12)(Rn), -N(R12)C(O)R12-N(R12)C(O)OR12, - N(R12)C(O)N(R12)(Rn), -N(R12)S(O)2(R12), -S(O)R12. -S(O)2R12, -S(O)2N(R12)(RU), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, and optionally substituted bicyclic heteroaryl; orRY1and RY2are taken together with the carbons to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl; orRY3and RY4are taken together with the carbons to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl; m is 0, 1, 2, 3, or 4; andp is 0 or 1; and(b) an additional agent, wherein the combined amount of the compound of Formula (IV a), or a pharmaceutically acceptable salt thereof, and the additional agent is therapeutically effective for treating the cancer.2. The method of embodiment 1, wherein the compound of Formula (IV a) is selected from Table 1.3. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) an amount of a compound of Formula (IVa-2)Formula (IVa-2) or a pharmaceutically acceptable salt thereof, wherein,Y1is N or CRY1;Y2is N or CRY2;Y3is N or CRY3;Y4is N or CRY4;R1is hydrogen, -CN, optionally substituted Ci-6 alky l, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C2-7heterocycloalkyk ring A is monocyclic heteroaryl, bicyclic heteroaryl, monocyclic heterocycloalkyl, or bicyclic heterocycloalkyd; each ofRAis independently selected from halogen, -NO2, oxo, -CN, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyd, -OR11, -SR11, -N(R12)(Rn), - C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)(Rn), -C(O)N(R12)(Rn), - N(R12)C(O)R12-N(R12)C(O)OR12. -N(R12)C(O)N(R12)(RU), -N(R12)2S(O)2(R12), - S(O)R12, -S(O)2R12, and -S(O)2N(R12)(R11);R11is hydrogen, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C1-4 alkylene-Cs-s cycloalkyl. optionally substituted -C 1-4 alkylene-C2-7 heterocycloalkyl, optionally substituted -Ci-4 alkylene-phenyl, or optionally substituted -C 1-4 alkyleneheteroaryl; each of R12is independently selected from hydrogen, -NO2, -CN, Ci-6 alkyl, Ci-6 aminoalkyl, Ci-e hydroxyalkyl. Ci-ehaloalkyl, C1-6 heteroalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, amino, -NO2, -CN, Ci-6 alkyl, C1-6 alkoxy, and Ci-6 haloalkyl;RB1is optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic lieteroar l: each of RY1, RY2. RY3and R4is independently selected from hydrogen, halo, -CN. - NO2, -OR11, -SR11, -N(R12)(Rn), optionally substituted Ci-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, -OR11, -SR11, -N(R12)(Rn), -C(O)R12, -C(O)OR12, -OC(O)R12, - OC(O)N(Rl2)(Rn). -C(O)N(R12)(R”), -N(R12)C(O)R12-N(R12)C(O)OR12, - N(R12)C(O)N(R12)(R11), -N(R12)S(O)2(R12), -S(O)R12. -S(O)2R12, -S(O)2N(R12)(Rn), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, and optionally substituted bicyclic heteroaryl; orRY1and RY2are taken together with the carbons to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl; orRY?and RY4are taken together with the carbons to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl; and m is 0, 1, 2, 3, or 4; and(b) an amount of an additional agent.I l l4. The method of embodiment 3, wherein the combined amount of the compound of Formula (IVa-2) or the pharmaceutically acceptable salt thereof and the additional agent are therapeutically effective.5. The method of any one of embodiments 1 -4. wherein the compound is selected from the group consisting of:and pharmaceutically acceptable salts thereof.6. The method of any one of embodiments 1-5. wherein the compound is(Compound 1) or a pharmaceutically acceptable salt thereofThe method of any one of embodiments 1-5, wherein the compound is(Compound 3) or a pharmaceutically acceptable salt thereof. The method of any one of embodiments 1-5. wherein the compound is(Compound 4) or a pharmaceutically acceptable salt thereof. The method of any one of embodiments 1-5, wherein the compound is(Compound 5) or a pharmaceutically acceptable salt thereof. The method of any one of embodiments 1-5, wherein the compound is(Compound 6) or a pharmaceutically acceptable salt thereof. The method of any one of embodiments 1-5. wherein the compound is(Compound 7) or a pharmaceutically acceptable salt thereof.The method of any one of embodiments 1-5, wherein the compound is(Compound 8) or a pharmaceutically acceptable salt thereof. The method of any one of embodiments 1-5, wherein the compound is(Compound 9) or a pharmaceutically acceptable salt thereof. The method of any one of embodiments 1-5, wherein the compound is(Compound 10) or a pharmaceutically acceptable salt thereof. The method of any one of embodiments 1-5, wherein the compound is(Compound 11) or a pharmaceutically acceptable salt thereof.The method of any one of embodiments 1-5, wherein the compound is(Compound 15) or a pharmaceutically acceptable salt thereof. The method of any one of embodiments 1-5. wherein the compound is(Compound 17) or a pharmaceutically acceptable salt thereof. The method of any one of embodiments 1-5, wherein the compound is(Compound 18) or a pharmaceutically acceptable salt thereof. The method of any one of embodiments 1-5. wherein the compound is(Compound 24) or a pharmaceutically acceptable salt thereof. The method of any one of embodiments 1-5. wherein the compound is(Compound 25) or a pharmaceutically acceptable salt thereof.The method of any one of embodiments 1-5, wherein the compound is(Compound 27) or a pharmaceutically acceptable salt thereof. The method of any one of embodiments 1 -5. wherein the compound is(Compound 28) or a pharmaceutically acceptable salt thereof. The method of any one of embodiments 1 -5. wherein the compound is(Compound 30) or a pharmaceutically acceptable salt thereof. The method of any one of embodiments 1-5, wherein the compound is(Compound 31) or a pharmaceutically acceptable salt thereof.The method of any one of embodiments 1-5, wherein the compound is(Compound 32) or a pharmaceutically acceptable salt thereof. The method of any one of embodiments 1-25, wherein the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, and breast cancer. The method of embodiment 26, wherein the cancer is ovarian or breast cancer. The method of embodiment 27, wherein the cancer is ovarian cancer. The method of embodiment 27, wherein the cancer is breast cancer. The method of any one of embodiments 1-29, wherein the cancer comprises cancer cells with elevated levels of RAD 18. The method of any one of embodiments 1-30, wherein the cancer is a DNA damage repair pathway deficient cancer, a PARP inhibitor resistant cancer, a PARP inhibitor refractory cancer, a BRCA1 mutant cancer, a BRCA1 -deficient cancer, and / or BRCA2 mutant cancer. The method of any one of embodiments 1-31, wherein the cancer is a DNA damage repair pathway deficient cancer. The method of any one of embodiments 1-32, wherein the cancer is a PARP inhibitor resistant or refractory cancer. The method of any one of embodiments 1-33, wherein the cancer is a BRCA1 mutant cancer and / or a BRCA2 mutant cancer. The method of embodiment 34, wherein the cancer is a BRC Al -deficient cancer. The method of any one of embodiments 1-35, wherein the additional agent is a DNA Damage Response Pathway (DDR) inhibitor, an mTOR inhibitor, an immune checkpoint inhibitor, a cell cycle inhibitor, a radiopharmaceutical agent, an anti-angiogenic agent, an antitubulin agent, a DNA synthesis inhibitor, a DNA alkylating agent, a topoisomerase inhibitor, a chemotherapeutic agent, or any combination thereof. The method of embodiment 36, wherein the additional agent is a DDR inhibitor.The method of embodiment 37, wherein the DDR pathway inhibitor is a PARP inhibitor, an ATM inhibitor, an ATR inhibitor, a WEE1 inhibitor, an APE1 inhibitor, a CHK1 inhibitor, or any combination thereof. The method of embodiment 38, wherein the DDR pathway inhibitor is a PARP inhibitor. The method of embodiment 39, wherein the PARP inhibitor is olaparib (AZD2281), veliparib (ABT-888), rucaparib, talazoparib (BMN 673), AG-14361, INO-1001 (3- aminobenzamide), A-966492, PJ34 HC1, niraparib, UPF 1069, ME0328, RK-287107, pamiparib (BGB-290), NMS-P118, E7449, picolinamide, benzamide, NU1025, iniparib (BSI-201), AZD2461, BGP-15 2HC1, XAV-939, 4-hydroxyquinazoline, NVP- TNKS656, MN 64, G007-LK, CEP-9722, CEP-8983, E7016, BYK204165, CEP-6800, DR2313, KU-0058684, L-2286, NU1064, NU1085, PUM00199, LT-673, MP-124, PF- 1367338, AG014699, KU-59436, 4-HQN, fluzoparib (SHR-3162), AMXI-5001, AZD9574, CVL218, IDX-1197, senaparib (IMP4297), JPI-547. NMS-03305293, RBN- 3143, RP12146, SC10914, TQB3823, or a pharmaceutically acceptable salt thereof. The method of claim 39, wherein the wherein the DDR pathway inhibitor is a PARP inhibitor selected from saruparib (AZD5305), olaparib (AZD2281), rucaparib, niraparib, talazoparib (BMN 673), or a pharmaceutically acceptable salt thereof The method of embodiment39. wherein the PARP inhibitor is olaparib (AZD2281), rucaparib, niraparib, talazoparib (BMN 673), or a pharmaceutically acceptable salt thereof. The method of embodiment 42, wherein the PARP inhibitor is olaparib (AZD2281) or a pharmaceutically acceptable salt thereof. The method of embodiment 38, wherein the DDR pathway inhibitor is an ATM inhibitor. The method of embodiment 44, wherein the ATM inhibitor is KU-55933, KU- 60019, wortmannin, torin 2, CP-466722, ETP -46464, CGK 733, AZ32. AZD1390, AZ31, AZD0156, or a pharmaceutically acceptable salt thereof. The method of embodiment 38, wherein the DDR pathway inhibitor is an ATR inhibitor. The method of embodiment 46, wherein the ATR inhibitor is RP-3500, M-6620, berzosertib (M-6620, VX-970; VE-822), AZD-6738, AZ-20, M-4344 (VX-803), BAY- 1895344, M-1774, IMP-9064, nLs-BG-129, SC-0245. BKT-300, ART-0380, ATRN-119, ATRN-212. NU-6027, or a pharmaceutically acceptable salt thereof. The method of embodiment 38, wherein the DDR pathway inhibitor is a WEE1 inhibitor. The method of embodiment 48, wherein the WEE1 inhibitor is AZD1775 (MK1775), ZN-c3, debio 0123, IMP7068, SDR-7995, SDR-7778. NUV-569, PD0166285,PD0407824, SC-0191, DC-859 / A, bosutinib, Bos-L or a pharmaceutically acceptable salt thereof. The method of embodiment 38, wherein the DDR pathway inhibitor is an APE1 inhibitor. The method of embodiment 50, wherein the APE1 inhibitor is CRT0044876. AJAY-4. E3330 / APX3330, APX2009, APE1 inhibitor III, or a pharmaceutically acceptable salt thereof. The method of embodiment 38, wherein the DDR pathway inhibitor is a CHK1 inhibitor. The method of embodiment 52, wherein the CHK1 inhibitor is AZD7762, rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, VX-803 (M4344), GDC- 0575 (ARRY-575), SAR-020106, CCT245737, PD0166285, prexasertib (LY2606368), or a pharmaceutically acceptable salt thereof. The method of embodiment 36, wherein the additional agent is an mTOR inhibitor. The method of embodiment 54, wherein the mTOR inhibitor is dactolisib (BEZ235), rapamycin (sirolimus), everolimus (RAD001), AZD8055, temsirolimus (CCI- 779), PI- 103, KU-0063794, torkinib (PP242), ridaforolimus (deforolimus, MK-8669), sapanisertib (MLN0128), voxtalisib (XL765), torin 1, torin 2, omipalisib (GSK2126458), OSI-027. PF-04691502, apitohsib (GDC-0980). GSK1059615, gedatolisib (PKI-587), WYE-354, vistusertib (AZD2014), WYE-125132 (WYE-132), PP121, WYE-687, WAY-600, ETP -46464, GDC-0349, XL388, GNE-477, bimirahsib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC 223), voxtalisib (XL765), zotarolimus (ABT-578), Tacrolimus (FK506). BGT226 maleate (NVP-BGT226 maleate), palomid 529 (P529), LY3023414 (samotolisib), biolimus-7, biolimus-9, azathioprine, campath 1H, chrysophanic acid, or a pharmaceutically acceptable salt thereof. The method of embodiment 36, wherein the additional agent is an immune checkpoint inhibitor. The method of embodiment 56, wherein the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, AMP -224, PF- 06801591, MEDI0680, PDR001, REGN2810, SHR-12-1, TSR-042, CA-170, atezolizumab, durvalumab, KN035, and BMS-936559, ipihmumab. tremelimumab, AGEN1884. AGEN2041. BMS-986016, GSK2831781, IMP321, LAG525, MGD013, TSR- 022, or a pharmaceutically acceptable salt thereof. The method of embodiment 36, wherein the additional agent is a cell cycle inhibitor.The method of embodiment 58, wherein the cell cycle inhibitor is a CDK 4 / 6 inhibitor, a CDK7 inhibitor, a CDK9 inhibitor, or any combination thereof. The method of embodiment 59, wherein the cell cycle inhibitor is a CDK 4 / 6 inhibitor. The method of embodiment 60, wherein the CDK 4 / 6 inhibitor is palbociclib (PD- 0332991), alvocidib. AT7519. JNJ-7706621, PHA-793887. BMS-265246, milcichb (PHA-848125), R547, rivicichb (P276-00), MCI 80295, G1T38, abemaciclib, ON123300, AT7519, purvalanol A, SU9516, ribociclib (LEE011), BSJ-03-123, or a pharmaceutically acceptable salt thereof. The method of embodiment 59, wherein the cell cycle inhibitor is a CDK7 inhibitor. The method of embodiment 62, wherein the CDK7 inhibitor is LDC4297, THZ1, THZ2, YKL-5-124, BS-181, samuraciclib, LY3405105, PHA-793887, SNS-032 (BMS- 387032), PF-562271, milciclib (PHA-848125), or a pharmaceutically acceptable salt thereof. The method of embodiment 59, wherein the cell cycle inhibitor is a CDK9 inhibitor. The method of embodiment 64, wherein the CDK9 inhibitor is SNS-032 (BMS-387032), LY2857785, alvocidib, or riviciclib hydrochloride (P276-00), or a pharmaceutically acceptable salt thereof. The method of embodiment 36, wherein the additional agent is a radiopharmaceutical agent. The method of embodiment 66, wherein the radiopharmaceutical agent comprises a radioisotope. The method of embodiment 36, wherein the additional agent is an anti-angiogenic agent. The method of embodiment 68, wherein the anti-angiogenic agent is a VEGF inhibitor, a VEGFR inhibitor, or the combination thereof. The method of embodiment 36, wherein the anti-angiogenic agent is bevacizumab, cediranib, axitinib, anginex, sunitinib, sorafenib, pazopanib. vatalanib, cabozantinib, ponatinib, lenvatinib, SU6668, everolimus, lenalidomide, ramucirumab, regorafenib, thalidomide, vandetanib, ziv-aflibercept, or a pharmaceutically acceptable salt thereof. The method of embodiment 36, wherein the additional agent is an antitubulin agent. The method of embodiment 71, wherein the antitubulin agent is a vinca alkaloid, colchicine, a taxane, or any combination thereof. The method of embodiment 72, wherein the antitubulin agent is a taxane. The method of embodiment 73, wherein the taxane is docetaxel, paclitaxel, accatin III,10-deacetyltaxol, 7-xylosyl-10-deacetyltaxol, chalcomenite. 10-deacetyl-7-epitaxol, 7-epitaxol, 10-deacetylbaccatin III, 10-deacetyl chalcomenite, or a pharmaceutically acceptable salt thereof. The method of embodiment 71, wherein the anti tubulin agent is a vinca alkaloid. The method of embodiment 74, wherein the vinca alkaloid is vinorelbine. vincristine, vinblastine, vinblastine N-oxide. vindesine, vinflunine, vincamine, vintafolide. deacetoxy vinzoli dine, or a pharmaceutically acceptable salt thereof. The method of embodiment 36, wherein the additional agent is a DNA synthesis inhibitor. The method of embodiment 77, wherein the DNA synthesis inhibitor is 5 -fluorouracil (5- FE1), 6-mercaptopurine (6- MP), capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, pemetrexed, or a pharmaceutically acceptable salt thereof. The method of embodiment 36, wherein the additional agent is a DNA alkylating agent. The method of embodiment 79, wherein the alkylating agent is altretamine, bendamustine, busulfan, improsulfan, piposulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, oxaliplatin, temozolomide, thiotepa, trabectedin, platinum coordination complexes, or a pharmaceutically acceptable salt thereof. The method of embodiment 36, wherein the additional agent is a topoisomerase inhibitor. The method of embodiment 81, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor, a topoisomerase II inhibitor, or the combination thereof. The method of embodiment 81, wherein the topoisomerase inhibitor is epipodopyyllotoxin, irinotecan, SN-38, ARC, NPC, camptothecin, topotecan, 9- nitrocamptothecin, exatecan, lurtotecan, lamellarin D9- aminocamptothecin, rubifen, gimatecan, diflomotecan, BN80927, DX-8951f, MAG-CPT, thiotepa. cyclosphosphamide, amsacrine, etoposide, etoposide phosphate, teniposide, daunorubicin, mitoxantrone, amsacrine, ellipticines, aurintricarboxylic acid, doxorubicin, HU-331, or a pharmaceutically acceptable salt thereof. The method of embodiment 81, wherein the topoisomerase inhibitor is epipodopyyllotoxin, SN-38, ARC. NPC. camptothecin, topotecan, 9-nitrocamptothecin, exatecan, lurtotecan, lamellarin D9- aminocamptothecin, rubifen, gimatecan, diflomotecan, BN80927, DX-8951f, MAG-CPT, thiotepa, cyclosphosphamide, amsacrine, etoposide, etoposide phosphate, teniposide, daunorubicin, mitoxantrone,amsacrine, ellipticines. aurintricarboxylic acid, doxorubicin, HU-331, or a pharmaceutically acceptable salt thereof.85. The method of embodiment 36, wherein the additional agent is a chemotherapeutic agent.86. The method of embodiment 85, wherein the chemotherapeutic agent is a Platinum compound, a psoralen agent, mitomycin C (MMC), dipoxybutane (DEB), or a pharmaceutically acceptable salt thereof.87. The method of embodiment 85, wherein the chemotherapeutic agent is carboplatin. cisplatin, oxaliplatin, mitomycin C (MMC), dipoxybutane (DEB), or a pharmaceutically acceptable salt thereof.88. Use of a compound of Formula (IV a) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein the medicament is formulated for being administered in combination with an additional agent.89. Use of a compound of Formula (IV a) or a pharmaceutically acceptable salt thereof and an additional agent in the manufacture of a medicament for treating cancer.90. Use of a compound of Formula (IVa-2) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein the medicament is formulated for being administered in combination with an additional agent.91. Use of a compound of Formula (IVa-2) or a pharmaceutically acceptable salt thereof and an additional agent in the manufacture of a medicament for treating cancer.

[0311] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of treating cancer in a subject in need thereof the method comprising administering to the subject:(a) a compound of Formula (IVa), or a pharmaceutically acceptable salt thereof:Formula (IVa) wherein,Y1is N or CRY1;Y2is N or CRY2;Y3is N or CRY3;Y4is N or CRY4;R1is hydrogen. -CN. optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C2-7 heterocycloalkyk each of R4and R4is independently selected from hydrogen, halo. -CN, -OR11, -SR11, -N(R12)(RU), optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C 2-7 heterocycloalkyl; or R4and R4taken together form an oxo; or R4and R4taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; each of R5and R5is independently selected from hydrogen, halo, -CN, -OR11, -SR11, - N(R12)(RU), optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl; or R5and R5taken together form an oxo; or R5and R5taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; each of R6and R6is independently selected from hydrogen, halo, -CN, -OR11, -SR11, - N(RI2)(R"). optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl. optionally substituted C3-8 cycloalkyl, andoptionally substituted C2-7 heterocycloalkyl; or R6and R6taken together form an oxo; or R6and R6taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; each of R8and R9is independently selected from hydrogen, halo, -CN, optionally substituted Ci-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl; or R8and R9taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; ring A is monocyclic heteroaryl, bicyclic heteroaryl, monocyclic heterocycloalkyl, or bicyclic heterocycloalkyl; each ofRAis independently selected from halogen, -NO2, oxo, -CN, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, -OR11, -SR11, -N(R12)(Rn), - C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)(R11), -C(O)N(R12)(Rn), - N(R12)C(O)R12-N(R12)C(O)OR12, -N(R12)C(O)N(R12)(RU), -N(R12)2S(O)2(R12), - S(O)R12, -S(O)2R12, and -S(O)2N(R12)(Rn);R11is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C'2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C1-4 alkylene-Cs-s cycloalkyl, optionally substituted -C 1-4 alkylene-C2-7 heterocycloalkyl, optionally substituted -Ci-4 alkylene-phenyl, or optionally substituted -C1-4 alkyleneheteroaryl; each of R12is independently selected from hydrogen, -NO2, -CN, C1-6 alky l, Ci-6 aminoalkyl, Ci-e hydroxyalkyl, Ci-ehaloalkyl, C 1-6 heteroalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently' selected from halogen, -OH, oxo, amino, -NO2, -CN, Ci-6 alkyl, C1-6 alkoxy, and Ci-6 haloalkyl;RB1is optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; each of RY1, RY2, RY3and R4is independently selected from hydrogen, halo, -CN, - NO2, -OR11, -SR11, -N(R12)(Rn), optionally substituted Ci-6 alkyl, optionallysubstituted Ci-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2.6alkynyl, -OR11, -SR11, -N(R12)(Rn), -C(O)R12, -C(O)OR12, -OC(O)R12, - OC(O)N(R12)(Rn), -C(O)N(R12)(Rn), -N(R12)C(O)R12-N(R12)C(O)OR12, - N(R12)C(O)N(R12)(Rn), -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)(RU), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, and optionally substituted bicyclic heteroaryl; orRY1and RY2are taken together with the carbons to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl; orRY3and RY4are taken together with the carbons to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C 2-9 heterocycloalkyl; m is 0, 1, 2, 3, or 4; and p is 0 or 1; and(b) an additional agent, wherein the combined amount of the compound of Formula (IV a), or a pharmaceutically acceptable salt thereof and the additional agent is therapeutically effective for treating the cancer.

2. The method of claim 1, wherein the compound of Formula (IV a) is selected from Table 1.

3. The method of claim 1 or claim 2, wherein the compound is selected from the group consisting of:and pharmaceutically acceptable salts thereof.

4. The method of any one of claims 1-3, wherein the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC). colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, and breast cancer.

5. The method of claim 4, wherein the cancer is ovarian or breast cancer.

6. The method of any one of claims 1-5, wherein the cancer comprises cancer cells with elevated levels of RAD 18.

7. The method of any one of claims 1-6, wherein the cancer is a DNA damage repair pathway deficient cancer, a PARP inhibitor resistant cancer, a PARP inhibitor refractory cancer, a BRCAl mutant cancer, a BRCAl-deficient cancer, and / or a BRCA2 mutant cancer.

8. The method of any one of claims 1-7, wherein the additional agent is a topoisomerase inhibitor, a DNA Damage Response Pathway (DDR) inhibitor, an mTOR inhibitor, an immune checkpoint inhibitor, a cell cycle inhibitor, a radiopharmaceutical agent, an anti- angiogenic agent, an antitubulin agent, a DNA synthesis inhibitor, a DNA alkylating agent, a chemotherapeutic agent, or any combination thereof.

9. The method of claim 8, wherein the additional agent is a topoisomerase inhibitor selected from irinotecan, SN-38, epipodopyyllotoxin, ARC, NPC, camptothecin, topotecan, 9- nitrocamptothecin, exatecan, lurtotecan, lamellarin D9- aminocamptothecin, rubifen, gimatecan, diflomotecan, BN80927, DX-8951f, MAG-CPT, thiotepa. cyclosphosphamide, amsacrine, etoposide, etoposide phosphate, teniposide, daunorubicin, mitoxantrone, amsacrine, ellipticines, aurintricarboxylic acid, doxorubicin, HU-331, and pharmaceutically acceptable salts thereof.

10. The method of claim 8, wherein the additional agent is a DDR pathway inhibitor.

11. The method of claim 10, wherein the DDR pathway inhibitor is a PARP inhibitor, an ATM inhibitor, an ATR inhibitor, a WEE1 inhibitor, an APE1 inhibitor, a CHK1 inhibitor, or any combination thereof.

12. The method of claim 11, wherein the wherein the DDR pathway inhibitor is a PARP inhibitor selected from saruparib (AZD5305), olaparib (AZD2281). rucaparib, niraparib. talazoparib (BMN 673), or a pharmaceutically acceptable salt thereof.

13. The method of claim 8, wherein the additional agent is a chemotherapeutic agent.

14. The method of claim 13, wherein the chemotherapeutic agent is carboplatin, cisplatin, oxaliplatin, a psoralen agent, mitomycin C (MMC), dipoxybutane (DEB), or a pharmaceutically acceptable salt thereof.

15. Use of a compound of Formula (IV a) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein the medicament is formulated for being administered in combination with an additional agent.

16. Use of a compound of Formula (IV a) or a pharmaceutically acceptable salt thereof and an additional agent in the manufacture of a medicament for treating cancer.

17. Use of a compound of Formula (IVa-2) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein the medicament is formulated for being administered in combination with an additional agent.

18. Use of a compound of Formula (IVa-2) or a pharmaceutically acceptable salt thereof and an additional agent in the manufacture of a medicament for treating cancer.

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