PARP1 inhibitors and uses thereof

Abstract

Described herein are PARP1 inhibitors and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for the treatment of cancer.

Description

CROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application Serial No. 63 / 176,610 filed April 19, 2021, U. S. Provisional Application Serial No. 63 / 183,563 filed May 03, 2021, and U. S. Provisional Application Serial No. 63 / 254,832 filed October 12, 2021 which are hereby incorporated by reference in their entirety. BACKGROUND OF THE INVENTION

[0002] Poly(ADP-ribose)polymerase (PARP) or poly(ADP-ribose)synthase (PARS) has an essential role in facilitating DNA repair, controlling RNA transcription, mediating cell death, and regulating immune response. These actions make PARP inhibitors targets for a broad spectrum of disorders. PARP inhibitors have demonstrated efficacy in numerous models of disease, particularly in models of ischemia reperfusion injury, inflammatory disease, degenerative diseases, protection from adverse effects of cytotoxic compounds, and the potentiation of cytotoxic cancer therapy. PARP has also been indicated in retroviral infection and thus inhibitors may have use in antiretroviral therapy. PARP inhibitors have been efficacious in preventing ischemia reperfusion injury in models of myocardial infarction, stroke, other neural trauma, organ transplantation, as well as reperfusion of the eye, kidney, gut and skeletal muscle. Inhibitors have been efficacious in inflammatory diseases such as arthritis, gout, inflammatory bowel disease, CNS inflammation such as MS and allergic encephalitis, sepsis, septic shock, hemorrhagic shock, pulmonary fibrosis, and uveitis. PARP inhibitors have also shown benefit in several models of degenerative disease including diabetes (as well as complications) and Parkinson’s disease. PARP inhibitors can ameliorate the liver toxicity following acetaminophen overdose, cardiac and kidney toxicities from doxorubicin and platinum based antineoplastic agents, as well as skin damage secondary to sulfur mustards. In various cancer models, PARP inhibitors have been shown to potentiate radiation and chemotherapy by increasing cell death of cancer cells, limiting tumor growth, decreasing metastasis, and prolonging the survival of tumor-bearing animals.

[0003] PARP 1 and PARP2 are the most extensively studied PARPs for their role in DNA damage repair. PARP1 is activated by DNA damage breaks and functions to catalyze the addition of poly (ADP-ribose) (PAR) chains to target proteins. This post-translational modification, known as PARylation, mediates the recruitment of additional DNA repair factors to DNA lesions.

[0004] Following completion of this recruitment role, PARP auto-PARylation triggers the release of bound PARP from DNA to allow access to other DNA repair proteins to complete repair. Thus, the binding of PARP to damaged sites, its catalytic activity, and its eventual release from DNA are all important steps for a cancer cell to respond to DNA damage caused by chemotherapeutic agents and radiation therapy.

[0005] Inhibition of PARP family enzymes has been exploited as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. A number of pre-clinical and clinical studies have demonstrated that tumor cells bearing deleterious alterations of BRCA1 or BRCA2, key tumor suppressor proteins involved in double-strand DNA break (DSB) repair by homologous recombination (HR), are selectively sensitive to small molecule inhibitors of the PARP family of DNA repair enzymes. Such tumors have deficient homologous recombination repair (HRR) pathways and are dependent on PARP enzymes function for survival. Although PARP inhibitor therapy has predominantly targeted SRCA-mutated cancers, PARP inhibitors have been tested clinically in non-SRCA-mutant tumors, those which exhibit homologous recombination deficiency (HRD).

[0006] It is believed that PARP inhibitors having improved selectivity for PARP1 may possess improved efficacy and reduced toxicity compared to other clinical PARP1 / 2 inhibitors. It is believed also that selective strong inhibition of PARP 1 would lead to trapping of PARP 1 on DNA, resulting in DNA double strand breaks (DSBs) through collapse of replication forks in S-phase. It is believed also that PARP1 - DNA trapping is an effective mechanism for selectively killing tumor cells having HRD. An unmet medical need therefore exists for effective and safe PARP inhibitors. Especially PARP inhibitors having selectivity for PARP1. SUMMARY OF THE INVENTION

[0007] Disclosed herein is a compound of Formula (III”), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: O Formula (III”), wherein: RC1 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more RCa; each RCa is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two RCa on the same atom are taken together to form an oxo; RC2 is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; RC3 is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; each R7 is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; or two R7 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each R8 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R8 on the same carbon are taken together to form an oxo; or two R8 on the same carbon, adjacent carbons, or opposite carbons are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; n is 0-6; R12 is Ci-Cealkyl, Ci-Cedeuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each R11 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; q is 0-3; each Ra is independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each Rb is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; and each Rc and Rd are independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-C6hydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl.

[0008] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0009] Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, a hematological cancer, gastrointestinal cancer, or lung cancer.

[0010] Also disclosed herein is method of treating a cancer comprising a BRCA1 and / or a BRCA2 mutation in a subject in need thereof, the method comprising administering a compound of any one of claims 1-70, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the cancer the cancer is bladder cancer, brain & CNS cancers, breast cancer, cervical cancer, colorectal cancer, esophagus cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cavity cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterus cancer. INCORPORATION BY REFERENCE

[0011] 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. DETAILED DESCRIPTION OF THE INVENTION Definitions

[0012] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0013] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0014] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0015] “oxo” refers to =0.

[0016] “Carboxyl” refers to -COOH.

[0017] “Cyano” refers to -CN.

[0018] “Alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1 -propyl, 2-methyl-2-propyl, 2-methyl-1 -butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-l-propyl, 2-methyl-l-pentyl, 3-methyl-1-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-1- butyl, 2-ethyl-1 -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “Ci-Ce alkyl” or “Ci-ealkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-ioalkyl. In some embodiments, the alkyl is a Ci-ealkyl. In some embodiments, the alkyl is a Ci-salkyl. In some embodiments, the alkyl is a Ci-4alkyl. In some embodiments, the alkyl is a Ci-3alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0019] “Alkenyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation 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” or “C2-6alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0020] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” or “C2-ealkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0021] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0022] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0023] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). 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, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0024] “Cycloalkyl” refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (C3-C10 cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (C3-C6 cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (C3-C5 cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (C3-C4 cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3 - to 10-membered cycloalkyl or a 3 - to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls 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, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -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.

[0025] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0026] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0027] “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. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0028] “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. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0029] “Cyanoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more cyano group. In some embodiments, the alkyl is substituted with one cyano. In some embodiments, the alkyl is substituted with one or two cyanos. Cyanoalkyls include, for example, cyanomethyl.

[0030] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyl include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0031] “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, phosphorus, or combinations thereof. A heteroalkyl 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 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl 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 heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -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.

[0032] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may 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 may be optionally oxidized; the nitrogen atom may be optionally quatemized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-C15 heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (C2-C10 heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (C2-C6 heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, 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-l,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. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. 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). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 - to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5 - to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0033] “Heteroaryl” refers to 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, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may 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 may be optionally oxidized; the nitrogen atom may 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. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5membered 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-IH-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 may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0034] 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 may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and / or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.

[0035] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0036] “Treatment” of an individual (e.g. a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.

[0037] “Synergy” or “synergize” refers to an effect of a combination that is greater than additive of the effects of each component alone at the same doses.

[0038] As used herein, a “disease or disorder associated with PARP” or, alternatively, “a PARP-mediated disease or disorder” means any disease or other deleterious condition in which PARP, or a mutant thereof, is known or suspected to play a role.

[0039] As used herein, a “disease or disorder associated with PARP1” or, alternatively, “a PARP1-mediated disease or disorder” means any disease or other deleterious condition in which PARP, or a mutant thereof, is known or suspected to play a role. Compounds

[0040] Described herein are compounds of Formula (I), (I’), (II), (III), (III’), (III”), (IV), and (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof useful in the treatment of cancer.

[0041] Disclosed herein is a compound of Formula (F), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: O Formula (F), wherein: R1 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; X is N or CR2; R2 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; Z is N or CR4; R4 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; Y is N or CR5; R5 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; R6 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; each R7 is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; or two R7 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each R8 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R8 on the same carbon are taken together to form an oxo; or two R8 on the same carbon, adjacent carbons, or opposite carbons are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; n is 0-6; R12 is cycloalkyl or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each R11 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; q is 0-3; each Ra is independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -0CH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each Rb is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; and each Rc and Rd are independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-C6hydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl.

[0042] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (I), wherein: R1 is hydrogen, deuterium, halogen, -CN, -NO2, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; X is N or CR2; R2 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; or R1 and R2 are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; Z is N or CR4; R4 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; Y is N or CR5; R5 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; R6 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; each R7 is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; or two R7 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each R8 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R8 on the same carbon are taken together to form an oxo; or two R8 on the same carbon, adjacent carbons, or opposite carbons are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; n is 0-6; Ring A is 3- to 16-membered monocyclic, bicyclic, or tricyclic ring, optionally comprising 1 to 5 heteroatoms selected from the group consisting of O, N, S, P, or B; each RA is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -0C(=0)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=0)NRcRd, -NRbC(=0)Ra, -NRbC(=0)0Rb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=0)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more RAa; or two RA on the same atom are taken together to form an oxo; each RAa is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -0C(=0)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=0)NRcRd, -NRbC(=0)Ra, -NRbC(=0)0Rb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=0)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two RAa on the same atom are taken together to form an oxo; m is 0-6; each Ra is independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each Rb is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; and each Rc and Rd are independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-C6hydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; provided that at least one of X or Y is N; and

[0043] In some embodiments of a compound of Formula (I) or (I’), R1 is Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-C6alkynyl, or cycloalkyl.

[0044] In some embodiments of a compound of Formula (I) or (F), R1 is halogen or cycloalkyl.

[0045] In some embodiments of a compound of Formula (I) or (F), R1 is cycloalkyl.

[0046] In some embodiments of a compound of Formula (I) or (F), R1 is Ci-Cealkyl.

[0047] In some embodiments of a compound of Formula (I) or (F), X is N and Y is CR5.

[0048] In some embodiments of a compound of Formula (I) or (I’), R5 is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) or (F), R5 is hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (F), R5 is hydrogen.

[0049] In some embodiments of a compound of Formula (I) or (F), X is CR2 and Y is N.

[0050] In some embodiments of a compound of Formula (I) or (F), R2 is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) or (F), R2 is hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (F), R2 is hydrogen. In some embodiments of a compound of Formula (I) or (F), R2 is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (I’), R2 is Ci-Cealkyl.

[0051] In some embodiments of a compound of Formula (I) or (F), X is N and Y is N. In some embodiments of a compound of Formula (I) or (F), Z is N. In some embodiments of a compound of Formula (I) or (F), Z is CR4.

[0052] In some embodiments of a compound of Formula (I) or (F), R4 is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) or (F), R4 is hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (I’), R4 is hydrogen.

[0053] In some embodiments of a compound of Formula (I) or (F), R6 is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) or (F), R6 is hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (F), R6 is hydrogen.

[0054] In some embodiments of a compound of Formula (I) or (I’), each R7 is independently hydrogen, deuterium, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I) or (F), each R7 is hydrogen. In some embodiments of a compound of Formula (I) or (F), two R7 are taken together to form a cycloalkyl.

[0055] In some embodiments of a compound of Formula (I) or (F), each R8 is Ci-Cealkyl; or two R8 on the same carbon are taken together to form an oxo. In some embodiments of a compound of Formula (I) or (F), two R8 on opposite carbons are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (I) or (F), two R8 on the same carbon are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (I) or (F), two R8 on adjacent carbons are taken together to form a cycloalkyl.

[0056] In some embodiments of a compound of Formula (I) or (F), n is 0. In some embodiments of a compound of Formula (I) or (I’), n is 1. In some embodiments of a compound of Formula (I) or (I’), n is 2. In some embodiments of a compound of Formula (I) or (F), n is 3. In some embodiments of a compound of Formula (I) or (F), n is 4. In some embodiments of a compound of Formula (I) or (F), n is 5. In some embodiments of a compound of Formula (I) or (F), n is 6. In some embodiments of a compound of Formula (I) or (F), n is 0-3. In some embodiments of a compound of Formula (I) or (F), n is 1-3. In some embodiments of a compound of Formula (I) or (F), n is 1 or 2. In some embodiments of a compound of Formula (I) or (F), n is 1-4. In some embodiments of a compound of Formula (I) or (F), n is 2-4.

[0057] In some embodiments of a compound of Formula (I), Ring A is 3- to 7-membered monocyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[0058] In some embodiments of a compound of Formula (I), Ring A is phenyl.

[0059] In some embodiments of a compound of Formula (I), Ring A is 5- to 6-membered heteroaryl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[0060] In some embodiments of a compound of Formula (I), Ring A is 5-membered heteroaryl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[0061] In some embodiments of a compound of Formula (I), Ring A is 6-membered heteroaryl, comprising 1 to 3 heteroatoms that are N.

[0062] In some embodiments of a compound of Formula (I), Ring A is pyridinyl.

[0063] In some embodiments of a compound of Formula (I), Ring A is not pyridinyl.

[0064] The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3- to 7-membered cycloalkyl.

[0065] In some embodiments of a compound of Formula (I), Ring A is 3- to 7-membered heterocycloalkyl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[0066] In some embodiments of a compound of Formula (I), Ring A is 6- to 12-membered bicyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[0067] In some embodiments of a compound of Formula (I), Ring A is 6- to 12-membered bicyclic heterocycloalkyl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[0068] In some embodiments of a compound of Formula (I), Ring A is 6- to 12-membered bicyclic heteroaryl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[0069] In some embodiments of a compound of Formula (I), Ring A is 6- to 12-membered bicyclic partially saturated ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[0070] In some embodiments of a compound of Formula (I), each RA is independently deuterium, halogen, -CN, -OH, -ORa, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more RAa; or two RA on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I), each RA is independently deuterium, halogen, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more RAa; or two RA on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I), each RA is independently halogen, -C(=0)NRcRd, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), each RA is independently -C(=0)NRcRd. In some embodiments of a compound of Formula (I), RA is not -C(=0)NRcRd. In some embodiments of a compound of Formula (I), each RA is independently heteroaryl optionally and independently substituted with one or more RAa.

[0071] In some embodiments of a compound of Formula (I), each RAa is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two RAa on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I), each RAa is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl; or two RAa on the same atom are taken together to form an oxo.

[0072] In some embodiments of a compound of Formula (I), m is 0-4. In some embodiments of a compound of Formula (I), m is 0 or 1. In some embodiments of a compound of Formula (I), m is 2 or 3. In some embodiments of a compound of Formula (I), m is 1 or 2. In some embodiments of a compound of Formula (I), m is 0. In some embodiments of a compound of Formula (I), m is 1. In some embodiments of a compound of Formula (I), m is 2. In some embodiments of a compound of Formula (I), m is 3. In some embodiments of a compound of Formula (I), m is 4. In some embodiments of a compound of Formula (I), m is 5. In some embodiments of a compound of Formula (I), m is 6. In some embodiments of a compound of Formula (I),

[0075] . In some embodiments of a compound of Formula (I), . In some embodiments of a compound of Formula (I), (RA)m is (RA)m is

[0076] In some embodiments of a compound of Formula (F), each R11 is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (F), each R11 is independently deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl. In some embodiments of a compound of Formula (F), each R11 is independently halogen or Ci-Cealkyl. In some embodiments of a compound of Formula (F), each R11 is independently halogen.

[0077] In some embodiments of a compound of Formula (F), q is 0 or 1. In some embodiments of a compound of Formula (F), q is 1 or 2. In some embodiments of a compound of Formula (F), q is 0. In some embodiments of a compound of Formula (F), q is 1. In some embodiments of a compound of Formula (F), q is 2. In some embodiments of a compound of Formula (F), q is 3.

[0078] In some embodiments of a compound of Formula (F), R12 is cycloalkyl. In some embodiments of a compound of Formula (F), R12 is cycloalkyl.

[0079] In some embodiments of a compound of Formula (I), the compound is a compound of formula: ra wherein R1 is Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl; Y is N, CH, or CF; each A1 is independently CH, CD, CMe, CCF3, CC1, CF, or N; each RA is independently hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, NHMe, or NHCD3.

[0080] In some embodiments of a compound of Formula (I), the compound is a compound of formula: ra wherein R1 is Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl; Y is N, CH, or CF; each A1 is independently CH, CD, CMe, CCF3, CC1, CF, or N; each RA is independently hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, NHMe, or NHCD3.

[0081] In some embodiments of a compound of Formula (I), the compound is a compound of formula: ra wherein R1 is Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl; Y is N, CH, or CF; each A1 is independently CH, CD, CMe, CCF3, CC1, CF, or N; each RA is independently hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, NHMe, or NHCD3; A2 is O, NH, NMe, or NCD3; and A3 is N, CH, CF, or CD.

[0082] In some embodiments of a compound of Formula (I), the compound is a compound of formula: o wherein R1 is Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl; Y is N, CH, or CF; each A1 is independently CH, CD, CMe, CCF3, CC1, CF, or N; each RA is independently hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, NHMe, or NHCD3; A2 is O, NH, NMe, or NCD3; and A3 is N, CH, CF, or CD.

[0083] In some embodiments of a compound of Formula (I), the compound is a compound of formula: R12 , or wherein R1 is Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl; Y is N, CH, or CF; each A is independently CH, CD, CMe, CCF3, CC1, CF, or N; W is CH2, CF2, CD2, CHF, CHD; each R11 is independently hydrogen, deuterium, or halogen; and R12 is Ci-Cealkyl or Ci-Cedeuteroalkyl.

[0084] Also disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: O Formula (II), wherein: R1 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, or C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; X is N or CR2; R2 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; or R1 and R2 are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; Z is N or CR4; R4 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; Y is N or CR5; R5 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; R6 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; W1 is absent, -C(R7)2-, -O-, -S-, -NRW1-, -C(R7)2C(R7)2-, -C(R7)2NRW1-, -NRW1C(R7)2-, -C(R7)2O-, -OC(R7)2 , -C(R7)2S-, or -SC(R7)2-; each R7 is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; or two R7 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; RW1 is hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl; Ring B is 3- to 16-membered monocyclic, bicyclic, or tricyclic ring, optionally comprising 1 to 5 heteroatoms selected from the group consisting of O, N, S, P, or B; each RB is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -0C(=0)Ra, -0C(=0)0Rb, -0C(=0)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=0)2NRcRd, -NRcRd, -NRbC(=0)NRcRd, -NRbC(=0)Ra, -NRbC(=0)0Rb, -NRbS(=0)2Ra, -C(=0)Ra, -C(=0)0Rb, -C(=0)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more RBa; or two RB on the same atom are taken together to form an oxo; each RBa is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -0C(=0)Ra, -0C(=0)0Rb, -0C(=0)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=0)2NRcRd, -NRcRd, -NRbC(=0)NRcRd, -NRbC(=0)Ra, -NRbC(=0)0Rb, -NRbS(=0)2Ra, -C(=0)Ra, -C(=0)0Rb, -C(=0)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two RBa on the same atom are taken together to form an oxo; p is 0-6; W2 is absent, -C(R9)2-, -0-, -S-, -NRW2-, -C(R9)2C(R9)2-, -C(R9)2NRW2-, -NRW2C(R9)2-, -C(R9)2O-, -OC(R9)2 , -C(R9)2S-, or -SC(R9)2-; each R9 is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; or two R9 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; RW2 is hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl; each R11 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; q is 0-3; each Ra is independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -0CH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each Rb is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; and each Rc and Rd are independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, - C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-C6hydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; provided that

[0085] In some embodiments of a compound of Formula (II), R1 is Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, or cycloalkyl. In some embodiments of a compound of Formula (II), R1 is Ci-Cealkyl.

[0086] In some embodiments of a compound of Formula (II), X is CR2 and Y is CR5.

[0087] In some embodiments of a compound of Formula (II), X is N and Y is CR5.

[0088] In some embodiments of a compound of Formula (II), R5 is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (II), R5 is hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (II), R5 is hydrogen.

[0089] In some embodiments of a compound of Formula (II), X is CR2 and Y is N.

[0090] In some embodiments of a compound of Formula (II), R2 is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (II), R2 is hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (II), R2 is hydrogen.

[0091] In some embodiments of a compound of Formula (II), X is N and Y is N.

[0092] In some embodiments of a compound of Formula (II), Z is N. In some embodiments of a compound of Formula (II), Z is CR4.

[0093] In some embodiments of a compound of Formula (II), R4 is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (II), R4 is hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (II), R4 is hydrogen.

[0094] In some embodiments of a compound of Formula (II), R6 is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (II), R6 is hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (II), R6 is hydrogen.

[0095] In some embodiments of a compound of Formula (II), W1 is -C(R7)2-, -NRW1-, -C(R7)2C(R7)2-, -C(R7)2NRW1-, or -NRW1C(R7)2-. In some embodiments of a compound of Formula (II), W1 is -C(R7)2-, -NRW1-, or -C(R7)2NRW1-. In some embodiments of a compound of Formula (II), W1 is -C(R7)2-.

[0096] In some embodiments of a compound of Formula (II), each R7 is independently hydrogen, deuterium, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (II), each R7 is hydrogen. In some embodiments of a compound of Formula (II), two R7 are taken together to form a cycloalkyl.

[0097] In some embodiments of a compound of Formula (II), RW1 is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (II), Rwlis hydrogen.

[0098] In some embodiments of a compound of Formula (II), W2 is absent, -C(R9)2-, -NRW2-, -C(R9)2C(R9)2-, -C(R9)2NRW2-, or -NRW2C(R9)2-.

[0099] In some embodiments of a compound of Formula (II), W1 is absent or -NRW2-. In some embodiments of a compound of Formula (II), W2 is absent. In some embodiments of a compound of Formula (II), W2 is -O-.

[00100] In some embodiments of a compound of Formula (II), each R9 is independently hydrogen, deuterium, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (II), each R9 is hydrogen. In some embodiments of a compound of Formula (II), two R799 are taken together to form a cycloalkyl.

[00101] In some embodiments of a compound of Formula (II), RW2 is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (II), RW2is hydrogen.

[00102] The compound of any one of claims 50-81, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is 3- to 7-membered monocyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[00103] In some embodiments of a compound of Formula (II), Ring B is 3- to 7-membered cycloalkyl.

[00104] In some embodiments of a compound of Formula (II), Ring B is 3- to 7-membered heterocycloalkyl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[00105] In some embodiments of a compound of Formula (II), Ring B is piperazinyl.

[00106] In some embodiments of a compound of Formula (II), Ring B is not piperazinyl.

[00107] In some embodiments of a compound of Formula (II), Ring B is 6- to 12-membered bicyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[00108] In some embodiments of a compound of Formula (II), Ring B is 6- to 12-membered bicyclic heterocycloalkyl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[00109] In some embodiments of a compound of Formula (II), Ring B is 6- to 12-membered bicyclic heterocycloalkyl, comprising 1 to 3 heteroatoms that are N.

[00110] In some embodiments of a compound of Formula (II), Ring B is 6- to 16-membered tricyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[00111] In some embodiments of a compound of Formula (II), Ring B is 6- to 16-membered tricyclic heterocycloalkyl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[00112] In some embodiments of a compound of Formula (II), Ring B is 6- to 16-membered tricyclic heterocycloalkyl, comprising 1 to 3 heteroatoms that are N.

[00113] In some embodiments of a compound of Formula (II), each RB is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl; or two RB on the same atom are taken together to form an oxo.

[00114] In some embodiments of a compound of Formula (II), each RB is independently deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl; or two RB on the same atom are taken together to form an oxo.

[00115] In some embodiments of a compound of Formula (II), p is 0-4. In some embodiments of a compound of Formula (II), p is 0 or 1. In some embodiments of a compound of Formula (II), p is 1 or 2. In some embodiments of a compound of Formula (II), p is 1. In some embodiments of a compound of Formula (II), p is 2. In some embodiments of a compound of Formula (II), p is 3. In some embodiments of a compound of Formula (II), p is 4.

[00118] In some embodiments of a compound of Formula (II), each R11 is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II), each R11 is independently deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl. In some embodiments of a compound of Formula (II), each R11 is independently halogen or Ci-Cealkyl.

[00119] In some embodiments of a compound of Formula (II), q is 0 or 1. In some embodiments of a compound of Formula (II), q is 1 or 2. In some embodiments of a compound of Formula (II), q is 1. In some embodiments of a compound of Formula (II), q is 0. In some embodiments of a compound of Formula (II), q is 2. In some embodiments of a compound of Formula (II), q is 3.

[00120] Also disclosed herein is a compound of Formula (III”), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (III”), wherein: RC1 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more RCa; each RCa is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two RCa on the same atom are taken together to form an oxo; RC2 is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, Q-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; RC3 is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; each R7 is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; or two R7 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each R8 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R8 on the same carbon are taken together to form an oxo; or two R8 on the same carbon, adjacent carbons, or opposite carbons are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; n is 0-6; R12 is Ci-Cealkyl, Ci-Cedeuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each R11 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; q is 0-3; each Ra is independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each Rb is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; and each Rc and Rd are independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-C6hydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl.

[00121] In some embodiments of a compound of Formula (III”), RC1 is deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more RCa. In some embodiments of a compound of Formula (III”), RC1 is halogen, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III”), RC1 is halogen, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III”), RC1 is halogen or cycloalkyl. In some embodiments of a compound of Formula (III”), RC1 is halogen. In some embodiments of a compound of Formula (III”), RC1 is cycloalkyl.

[00122] In some embodiments of a compound of Formula (III”), each RCa is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III”), each RCa is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-C6alkyl, or Ci-C6haloalkyl.

[00123] In some embodiments of a compound of Formula (III”), RC2 is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (III”), RC2 is hydrogen, deuterium, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (III”), RC2 is hydrogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (III”), RC2 is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (III”), RC2 is hydrogen. In some embodiments of a compound of Formula (III”), RC2 is Ci-Cealkyl.

[00124] In some embodiments of a compound of Formula (III”), RC3 is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (III”), RC3 is hydrogen, deuterium, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (III”), RC3 is hydrogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (III”), RC3 is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (III”), RC3 is hydrogen. In some embodiments of a compound of Formula (III”), RC3 is Ci-Cealkyl.

[00127] In some embodiments of a compound of Formula (III”), each R7 is independently hydrogen, deuterium, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (III”), each R7 is hydrogen. In some embodiments of a compound of Formula (III”), two R7 are taken together to form a cycloalkyl.

[00128] In some embodiments of a compound of Formula (III”), each R8 is Ci-Cealkyl; or two R8 on the same carbon are taken together to form an oxo. In some embodiments of a compound of Formula (III”), two R8 on opposite carbons are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (III”), two R8 on the same carbon are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (III”), two R8 on adjacent carbons are taken together to form a cycloalkyl.

[00129] In some embodiments of a compound of Formula (III”), n is 0. In some embodiments of a compound of Formula (III”), n is 1. In some embodiments of a compound of Formula (III”), n is 2. In some embodiments of a compound of Formula (III”), n is 3. In some embodiments of a compound of Formula (III”), n is 4. In some embodiments of a compound of Formula (III”), n is 5. In some embodiments of a compound of Formula (III”), n is 6. In some embodiments of a compound of Formula (III”), n is 0-3. In some embodiments of a compound of Formula (III”), n is 1-3. In some embodiments of a compound of Formula (III”), n is 1 or 2. In some embodiments of a compound of Formula (III”), n is 1-4. In some embodiments of a compound of Formula (III”), n is 2-4.

[00130] In some embodiments of a compound of Formula (III”), each R11 is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III”), each R11 is independently deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl. In some embodiments of a compound of Formula (III”), each R11 is independently halogen or Ci-Cealkyl. In some embodiments of a compound of Formula (III”), each R11 is independently halogen.

[00131] In some embodiments of a compound of Formula (III”), q is 0 or 1. In some embodiments of a compound of Formula (III”), q is 1 or 2. In some embodiments of a compound of Formula (III”), q is 0. In some embodiments of a compound of Formula (III”), q is 1. In some embodiments of a compound of Formula (III”), q is 2. In some embodiments of a compound of Formula (III”), q is 3.

[00132] In some embodiments of a compound of Formula (III”), R12 is Ci-Cealkyl or cycloalkyl. In some embodiments of a compound of Formula (III”), R12 is Ci-Cealkyl. In some embodiments of a compound of Formula (III”), R12 is cycloalkyl.

[00133] Also disclosed herein is a compound of Formula (IIF), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: O Formula (III’), wherein: Ring C is 3- to 16-membered monocyclic, bicyclic, or tricyclic ring, optionally comprising 1 to 5 heteroatoms selected from the group consisting of O, N, S, P, or B; each Rc is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -0C(=0)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=0)NRcRd, -NRbC(=0)Ra, -NRbC(=0)0Rb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=0)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more RCa; or two Rc on the same atom are taken together to form an oxo; each RCa is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -0C(=0)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=0)2NRcRd, -NRcRd, -NRbC(=0)NRcRd, -NRbC(=0)Ra, -NRbC(=0)0Rb, -NRbS(=0)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=0)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two RCa on the same atom are taken together to form an oxo; r is 0-6; W3 is absent, -C(R7)2-, or C2 alkynylene; each R7 is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; or two R7 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each R8 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -0C(=0)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=0)NRcRd, -NRbC(=0)Ra, -NRbC(=0)0Rb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=0)NRcRd, Ci-C6alkyl, CrChhaloalkyl. Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R8 on the same carbon are taken together to form an oxo; or two R8 on the same carbon, adjacent carbons, or opposite carbons are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; n is 0-6; A is N or CR11 or CH; R12 is Ci-Cealkyl or Ci-Cedeuteroalkyl; each R11 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; q is 0-3; each Ra is independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -0CH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each Rb is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; and each Rc and Rd are independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-C6hydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl;

[00134] Also disclosed herein is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (III), wherein: Ring C is 3- to 16-membered monocyclic, bicyclic, or tricyclic ring, optionally comprising 1 to 5 heteroatoms selected from the group consisting of O, N, S, P, or B; each Rc is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=0)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more RCa; or two Rc on the same atom are taken together to form an oxo; each RCa is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -0C(=0)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=0)NRcRd, -NRbC(=0)Ra, -NRbC(=0)0Rb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=0)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two RCa on the same atom are taken together to form an oxo; r is 0-6; W3 is absent, -C(R7)2-, or C2 alkynylene; each R7 is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; or two R7 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each R8 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R8 on the same carbon are taken together to form an oxo; or two R8 on the same carbon, adjacent carbons, or opposite carbons are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; n is 0-6; each R11 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; q is 0-3; each Ra is independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Cj-Garni noalkyl. G-Ghctcroalkyl. C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -0CH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, G-Galkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, G-Gaminoalkyl, or Ci-Ceheteroalkyl; each Rb is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; and each Rc and Rd are independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-C6hydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl;

[00135] In some embodiments of a compound of Formula (III) or (III’), Ring C is 3- to 7-membered monocyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[00136] In some embodiments of a compound of Formula (III) or (IIF), Ring C is phenyl.

[00137] In some embodiments of a compound of Formula (III) or (III’), Ring C is 5- to 6-membered heteroaryl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[00138] In some embodiments of a compound of Formula (III) or (IIF), Ring C is 5-membered heteroaryl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[00139] In some embodiments of a compound of Formula (III) or (IIF), Ring C is 6-membered heteroaryl, comprising 1 to 3 heteroatoms that are N.

[00140] In some embodiments of a compound of Formula (III) or (IIF), Ring C is 3- to 7-membered cycloalkyl.

[00141] In some embodiments of a compound of Formula (III) or (IIF), Ring C is 3- to 7-membered heterocycloalkyl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[00142] In some embodiments of a compound of Formula (III) or (IIF), Ring C is 6- to 12-membered bicyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[00143] In some embodiments of a compound of Formula (III) or (IIF), Ring C is 6- to 12-membered bicyclic heterocycloalkyl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[00144] In some embodiments of a compound of Formula (III) or (IIF), Ring C is 6- to 12-membered bicyclic heteroaryl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[00145] In some embodiments of a compound of Formula (III) or (IIF), Ring C is 8- to 16-membered tricyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[00146] In some embodiments of a compound of Formula (III) or (IIF), Ring C is 8- to 16-membered tricyclic heterocycloalkyl, comprising 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[00147] In some embodiments of a compound of Formula (III) or (IIF), each Rc is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; or two Rc on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (III) or (IIF), each Rc is independently deuterium, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl; or two Rc on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (III) or (IIF), each Rc is independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-C6alkynyl, or cycloalkyl. In some embodiments of a compound of Formula (III) or (IIF), each Rc is independently Ci-Cealkyl. In some embodiments of a compound of Formula (III) or (IIF), Rc is not Ci-Cealkyl. In some embodiments of a compound of Formula (III) or (IIF), Rc is not Ci-Cehaloalkyl.

[00148] In some embodiments of a compound of Formula (III) or (IIF), r is 0-4. In some embodiments of a compound of Formula (III) or (IIF), r is 1-3. In some embodiments of a compound of Formula (III) or (IIF), r is 0 or 1. In some embodiments of a compound of Formula (III) or (IIF), r is 0-3. In some embodiments of a compound of Formula (III) or (IIF), r is 1 or 2. In some embodiments of a compound of Formula (III) or (IIF), r is 1 or 2. In some embodiments of a compound of Formula (III) or (IIF), r is 1. In some embodiments of a compound of Formula (III) or (III’), r is 2. In some embodiments of a compound of Formula (III) or (IIF), r is 3. In some embodiments of a compound of Formula (III) or (IIF), r is 4.

[00151] In some embodiments of a compound of Formula (III) or (III’), W3 is absent. In some embodiments of a compound of Formula (III) or (IIF), W3 is C2 alkynylene. In some embodiments of a compound of Formula (III) or (IIF), W3 is -C(R7)2-.

[00152] In some embodiments of a compound of Formula (III) or (IIF), each R7 is independently hydrogen, deuterium, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (III) or (IIF), each R7 is hydrogen. In some embodiments of a compound of Formula (III) or (IIF), two R7 are taken together to form a cycloalkyl.

[00153] In some embodiments of a compound of Formula (III) or (IIF), each R8 is Ci-Cealkyl; or two R8 on the same carbon are taken together to form an oxo. In some embodiments of a compound of Formula (III) or (in’), two R8 on opposite carbons are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (III) or (III’), two R8 on the same carbon are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (III) or (IIF), two R8 on adjacent carbons are taken together to form a cycloalkyl.

[00154] In some embodiments of a compound of Formula (III) or (IIF), n is 0. In some embodiments of a compound of Formula (III) or (IIF), n is 1. In some embodiments of a compound of Formula (III) or (IIF), n is 2. In some embodiments of a compound of Formula (III) or (IIF), n is 3. In some embodiments of a compound of Formula (III) or (IIF), n is 4. In some embodiments of a compound of Formula (III) or (IIF), n is 5. In some embodiments of a compound of Formula (III) or (IIF), n is 6. In some embodiments of a compound of Formula (III) or (IIF), n is 0-3. In some embodiments of a compound of Formula (III) or (IIF), n is 1-3. In some embodiments of a compound of Formula (III) or (IIF), n is 1 or 2. In some embodiments of a compound of Formula (III) or (IIF), n is 1-4. In some embodiments of a compound of Formula (III) or (III’), n is 2-4.

[00155] In some embodiments of a compound of Formula (III) or (IIF), each R11 is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III) or (IIF), each R11 is independently deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl. In some embodiments of a compound of Formula (III) or (IIF), each R11 is independently halogen or Ci-Cealkyl.

[00156] In some embodiments of a compound of Formula (III) or (III’), q is 0 or 1. In some embodiments of a compound of Formula (III) or (IIF), q is 1 or 2. In some embodiments of a compound of Formula (III) or (in’), q is 0. In some embodiments of a compound of Formula (III) or (IIF), q is 1. In some embodiments of a compound of Formula (III) or (IIF), q is 2. In some embodiments of a compound of Formula (III) or (IIF), q is 3.

[00157] In some embodiments of a compound of Formula (III) or (IIF), the compound is a compound of formula:                         0 wherein Y is N, CH, or CF; A1 is CH2, CF2, CHF, CHCH3, C(CH3)2; B1 is CH2, CF2, CHF, CHCH3, C(CH3)2; and C1 is O or S; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00158] In some embodiments of a compound of Formula (III) or (III’), the compound is a compound of H h T Me formula:                         0 wherein Y is N, CH, or CF; A2 is CH2, CF2, CHF, CHCH3, C(CH3)2; B2 is CH2, CF2, CHF, CHCH3, C(CH3)2; and C2 is CH2, CF2, CHF, CHCH3, C(CH3)2; and D2 is O or S; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00159] In some embodiments of a compound of Formula (III) or (IIF), the compound is a compound of H formula:                          0 wherein Y is N, CH, or CF; A3 is hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or cycloalkyl optionally substituted with halogen; B3 is O or S; and C3 is hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, or cycloalkyl optionally substituted with halogen; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00160] In some embodiments of a compound of Formula (III) or (IIF), the compound is a compound of formula:                            0 wherein Y is N, CH, or CF; A4 is hydrogen, Ci-Cealkyl, or Ci-Cehaloalkyl; B4 is hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl; and C4 is O or S; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00161] In some embodiments of a compound of Formula (III) or (III’), the compound is a compound of formula: H 'Me wherein Y is N, CH, or CF; A5 is O or S; B5 is hydrogen, Ci-Cealkyl, or Ci-Cehaloalkyl; and C5 is hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00162] In some embodiments of a compound of Formula (III) or (III’), the compound is a compound of formula: wherein Y is N, CH, or CF; A6 is hydrogen, Ci-Cealkyl, or Ci-Cehaloalkyl; and B6 is O or S; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00163] In some embodiments of a compound of Formula (III) or (IIF), the compound is a compound of formula: wherein Y is N, CH, or CF; A7 is O or S; B7 is CH2, CF2, CHF, CHCH3, C(CH3)2; and C7 is CH2, CF2, CHF, CHCH3, C(CH3)2; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00164] In some embodiments of a compound of Formula (III) or (IIF), the compound is a compound of formula: wherein Y is N, CH, or CF; A8 is O or S; B8 is CH2, CF2, CHF, CHCH3, C(CH3)2; C7 is CH2, CF2, CHF, CHCH3, C(CH3)2; and D8 is CH2, CF2, CHF, CHCH3, C(CH3)2; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00165] In some embodiments of a compound of Formula (III) or (IIF), the compound is a compound of formula: wherein Y is N, CH, or CF; A9 is O or S; B9 is hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, or cycloalkyl optionally substituted with halogen; and C9 is hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or cycloalkyl optionally substituted with halogen; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00166] In some embodiments of a compound of Formula (III) or (III’), the compound is a compound of formula:                         0 wherein Y is N, CH, or CF; A is CH, CMe, CCF3, CC1, CF, or N; R12 is Ci-Cealkyl, Ci-Cedeuteroalkyl; each R11 is independently hydrogen, deuterium, or halogen; A10 is Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl.

[00167] Disclosed herein is a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (IV), wherein: R1 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; X is N or CR2; R2 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; or R1 and R2 are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; Z is N or CR4; R4 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; Y is N or CR5; R5 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; R6 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; R7a is deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; FCb is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; or R7a and R7b are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each R8 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R8 on the same carbon are taken together to form an oxo; or two R8 on the same carbon, adjacent carbons, or opposite carbons are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Cj-G>haloalkyl. Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, G-Gaminoalkyl. or Ci-Ceheteroalkyl; n is 0-6; each R11 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Gaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; q is 0-3; each Ra is independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each Rb is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; and each Rc and Rd are independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-C6hydroxyalkyl, Ci-Ceaminoalkyl, or CrGhctcroalkyl.

[00168] In some embodiments of a compound of Formula (IV), R1 is Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, or cycloalkyl. In some embodiments of a compound of Formula (IV), R1 is Ci-Cealkyl.

[00169] In some embodiments of a compound of Formula (IV), X is CR2 and Y is CR5.

[00170] In some embodiments of a compound of Formula (IV), X is N and Y is CR5.

[00171] In some embodiments of a compound of Formula (IV), R5 is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (IV), R5 is hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (IV), R5 is hydrogen.

[00172] In some embodiments of a compound of Formula (IV), X is CR2 and Y is N.

[00173] In some embodiments of a compound of Formula (IV), R2 is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (IV), R2 is hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (IV), R2 is hydrogen.

[00174] In some embodiments of a compound of Formula (IV), X is N and Y is N.

[00175] In some embodiments of a compound of Formula (IV), Z is N. In some embodiments of a compound of Formula (IV), Z is CR4.

[00176] In some embodiments of a compound of Formula (IV), R4 is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (IV), R4 is hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (IV), R4 is hydrogen.

[00177] In some embodiments of a compound of Formula (IV), R6 is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (IV), R6 is hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (IV), R6 is hydrogen.

[00178] In some embodiments of a compound of Formula (IV), R7a is deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl. In some embodiments of a compound of Formula (IV), R7a is deuterium or Ci-Cealkyl. In some embodiments of a compound of Formula (IV), R7a is deuterium.

[00179] In some embodiments of a compound of Formula (IV), R7b is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl. In some embodiments of a compound of Formula (IV), FVb is hydrogen, deuterium, or Ci-Cealkyl.

[00180] In some embodiments of a compound of Formula (IV), R7a and FVb are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (IV), R7a and FCb are deuterium.

[00181] In some embodiments of a compound of Formula (IV), each R8 is Ci-Cealkyl; or two R8 on the same carbon are taken together to form an oxo. In some embodiments of a compound of Formula (IV), two R8 on opposite carbons are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (IV), two R8 on the same carbon are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (IV), two R8 on adjacent carbons are taken together to form a cycloalkyl.

[00182] In some embodiments of a compound of Formula (IV), n is 0. In some embodiments of a compound of Formula (IV), n is 1. In some embodiments of a compound of Formula (IV), n is 2. In some embodiments of a compound of Formula (IV), n is 3. In some embodiments of a compound of Formula (IV), n is 4. In some embodiments of a compound of Formula (IV), n is 5. In some embodiments of a compound of Formula (IV), n is 6. In some embodiments of a compound of Formula (IV), n is 0-3. In some embodiments of a compound of Formula (IV), n is 1-3. In some embodiments of a compound of Formula (IV), n is 1 or 2. In some embodiments of a compound of Formula (IV), n is 1-4. In some embodiments of a compound of Formula (IV), n is 2-4.

[00183] In some embodiments of a compound of Formula (IV), each R11 is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (IV), each R11 is independently deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl. In some embodiments of a compound of Formula (IV), each R11 is independently halogen or Ci-Cealkyl.

[00184] In some embodiments of a compound of Formula (IV), q is 0 or 1. In some embodiments of a compound of Formula (IV), q is 1 or 2. In some embodiments of a compound of Formula (IV), q is 0. In some embodiments of a compound of Formula (IV), q is 1. In some embodiments of a compound of Formula (IV), q is 2. In some embodiments of a compound of Formula (IV), q is 3.

[00185] Disclosed herein is a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (V), wherein: R1 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; X is N or CR2; R2 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; or R1 and R2 are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; Z is N or CR4; R4 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; Y is N or CR5; R5 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; R6 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; each R7 is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; or two R7 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each R8 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R8 on the same carbon are taken together to form an oxo; or two R8 on the same carbon, adjacent carbons, or opposite carbons are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; n is 1-6; each R11 is independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; provided that one R11 and one R8 are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each A is independently N or CR11; R12 is Ci-Cealkyl or Ci-Cedeuteroalkyl; each Ra is independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each Rb is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; and each Rc and Rd are independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-C6hydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl.

[00186] In some embodiments of a compound of Formula (V), R1 is Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, C2-C6alkynyl, or cycloalkyl.

[00187] In some embodiments of a compound of Formula (V), R1 is Ci-Cealkyl.

[00188] In some embodiments of a compound of Formula (V), X is N and Y is CR5.

[00189] In some embodiments of a compound of Formula (V), R5 is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (V), R5 is hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (V), R5 is hydrogen.

[00190] In some embodiments of a compound of Formula (V), X is CR2 and Y is N.

[00191] In some embodiments of a compound of Formula (V), R2 is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (V), R2 is hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (V), R2 is hydrogen.

[00192] In some embodiments of a compound of Formula (V), X is N and Y is N. In some embodiments of a compound of Formula (V), Z is N. In some embodiments of a compound of Formula (V), Z is CR4.

[00193] In some embodiments of a compound of Formula (V), R4 is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (V), R4 is hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (V), R4 is hydrogen.

[00194] In some embodiments of a compound of Formula (V), R6 is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cecyanoalkyl, Ci-Ceheteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (V), R6 is hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (V), R6 is hydrogen.

[00195] In some embodiments of a compound of Formula (V), each R7 is independently hydrogen, deuterium, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (V), each R7 is hydrogen. In some embodiments of a compound of Formula (V), two R7 are taken together to form a cycloalkyl.

[00196] In some embodiments of a compound of Formula (V), each R8 is Ci-Cealkyl; or two R8 on the same carbon are taken together to form an oxo. In some embodiments of a compound of Formula (V), two R8 on opposite carbons are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (V), two R8 on the same carbon are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (V), two R8 on adjacent carbons are taken together to form a cycloalkyl.

[00197] In some embodiments of a compound of Formula (V), n is 0. In some embodiments of a compound of Formula (V), n is 1. In some embodiments of a compound of Formula (V), n is 2. In some embodiments of a compound of Formula (V), n is 3. In some embodiments of a compound of Formula (V), n is 4. In some embodiments of a compound of Formula (V), n is 5. In some embodiments of a compound of Formula (V), n is 6. In some embodiments of a compound of Formula (V), n is 0-3. In some embodiments of a compound of Formula (V), n is 1-3. In some embodiments of a compound of Formula (V), n is 1 or 2. In some embodiments of a compound of Formula (V), n is 1-4. In some embodiments of a compound of Formula (V), n is 2-4.

[00198] In some embodiments of a compound of Formula (V), each R11 is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (V), each R11 is independently deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl. In some embodiments of a compound of Formula (V), each R11 is independently halogen or Ci-Cealkyl.

[00199] In some embodiments of a compound of Formula (V), one A is CR11 and one is N. In some embodiments of a compound of Formula (V), both A are CR11. In some embodiments of a compound of Formula (V), both A are N.

[00200] In some embodiments of a compound of Formula (V), R12 is Ci-Cealkyl. In some embodiments of a compound of Formula (V), R12 is Ci-Cedeuteroalkyl.

[00201] In some embodiments of a compound of Formula (V), one R11 and one R8 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl.

[00202] In some embodiments of a compound of Formula (V), one R11 and one R8 are taken together to form a heterocycloalkyl optionally substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl.

[00203] In some embodiments of a compound of Formula (V), one R11 and one R8 are taken together to form a 5- or 6-membered heterocycloalkyl optionally substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl.

[00204] In some embodiments of a compound of Formula (V), one R11 and one R8 are taken together to form a 6-membered heterocycloalkyl optionally substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl.

[00205] In some embodiments of a compound of Formula (V), one R11 and one R8 are taken together to form a 5-membered heterocycloalkyl optionally substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl.

[00206] In some embodiments of a compound of Formula (V), the compound has the following formula: o wherein R1 is Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl; Y is N, CH, or CF; each A is independently CH, CD, CMe, CCF3, CC1, CF, or N; B1 is O, S, NH, NMe, NCD3, CH2, CHF, CD2, or CDH; R is hydrogen, deuterium, or halogen; and R12 is Ci-Cealkyl or Ci-Cedeuteroalkyl.

[00207] In some embodiments of a compound disclosed herein, each Ra is independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-C6hydroxyalkyl, Ci-Cgaminoalkyl, Ci-Cgheteroalkyl. In some embodiments of a compound disclosed herein, each Ra is independently Ci-Cealkyl, Ci-Cehaloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -0CH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl. In some embodiments of a compound disclosed herein, each Ra is independently Ci-Cealkyl, Ci-Cehaloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Ra is independently Ci-Cealkyl or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Ra is independently Ci-Cealkyl.

[00208] In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -0CH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-C6hydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen or Ci-Cealkyl.

[00209] In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-C6hydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen or Ci-Cealkyl.

[00210] In some embodiments of a compound disclosed herein, Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl.

[00211] In some embodiments of a compound disclosed herein, each RA, RB, Rc, Ra, Rb, Rc, Rd, the cycloalkyl or heterocycloalkyl formed when 2 R7 are taken together, the cycloalkyl or heterocycloalkyl formed when 2 R8 are taken together, and the heterocycloalkyl formed when Rc and Rd are taken together, is independently substituted with one, two, three, or four substituents as defined herein. In some embodiments of a compound disclosed herein, each RA, RB, Rc, Ra, Rb, Rc, Rd, the cycloalkyl or heterocycloalkyl formed when 2 R7 are taken together, the cycloalkyl or heterocycloalkyl formed when 2 R8 are taken together, and the heterocycloalkyl formed when Rc and Rd are taken together, is independently substituted with one, two, or three substituents as defined herein. In some embodiments of a compound disclosed herein, each RA, RB, Rc, Ra, Rb, Rc, Rd, the cycloalkyl or heterocycloalkyl formed when 2 R7 are taken together, the cycloalkyl or heterocycloalkyl formed when 2 R8 are taken together, and the heterocycloalkyl formed when Rc and Rd are taken together, is independently substituted with one or two substituents as defined herein. In some embodiments of a compound disclosed herein, each RA, RB, Rc, Ra, Rb, Rc, Rd, the cycloalkyl or heterocycloalkyl formed when 2 R7 are taken together, the cycloalkyl or heterocycloalkyl formed when 2 R8 are taken together, and the heterocycloalkyl formed when Rc and Rd are taken together, is independently substituted with one substituent as defined herein.

[00212] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[00213] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selected from a compound of Table 1. TABLE 1

[00214] In some embodiments, the compound is selected from the group consisting of: salt, solvate, or stereoisomer thereof.

[00215] In some embodiments, the compound is selected from the group consisting of: thereof.

[00216] In some embodiments, the compound is selected from the group consisting of: salt, solvate, or stereoisomer thereof.

[00217] In some embodiments, the compound is selected from the group consisting of: thereof. Me , and , or a pharmaceutically acceptable salt, solvate, or stereoisomer

[00218] In some embodiments, the compound is selected from the group consisting of: Further Forms of Compounds Disclosed Herein Isomers / Stereoisomers

[00219] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. Labeled compounds

[00220] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2H, 3H, 13C, 14C, 15N, 18O,17O,31P, 32P, 35S, 18F, and 36C1, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.

[00221] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Pharmaceutically acceptable salts

[00222] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[00223] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[00224] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate and xylenesulfonate.

[00225] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methane sulfonic acid, ethane sulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzene sulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct- 2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1 -carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.

[00226] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(Ci-4 alkyl)4, and the like.

[00227] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogencontaining groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization. Solvates

[00228] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[00229] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Tautomers

[00230] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Method of Treatment

[00231] Disclosed herein are methods of treatment of a disease in which inhibition of PARP is beneficial, the method comprising administering a compound disclosed herein. Also disclosed herein are methods of treatment of a disease in which inhibition of PARP 1 is beneficial, the method comprising administering a compound disclosed herein. In some embodiments, the disease is cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, a hematological cancer, a gastrointestinal cancer such as gastric cancer and colorectal cancer, or lung cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiment, the cancer is leukemia, colon cancer, glioblastoma, lymphoma, melanoma, or cervical cancer.

[00232] In some embodiments, the cancer comprises a BRCA1 and / or a BRCA2 mutation.

[00233] In some embodiments, the cancer comprising a BRCA1 and / or a BRCA2 mutation is bladder cancer, brain & CNS cancers, breast cancer, cervical cancer, colorectal cancer, esophagus cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cavity cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterus cancer.

[00234] In some embodiments, the cancer is a cancer deficient in Flomologous Recombination (FIR) dependent DNA DSB repair activity. The FIR dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via homologous mechanisms to reform a continuous DNA helix. The components of the FIR dependent DNA DSB repair pathway include, but are not limited to, ATM (NM_000051 ), RAD51 (NM_002875), RAD51 LI (NM_002877), RAD51 C (NM_002876), RAD51 L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431 ), XRCC3 (NM_005432), RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), MRE1 1 A (NM_005590) and NBS1 (NM_002485). Other proteins involved in the FIR dependent DNA DSB repair pathway include regulatory factors such as EMSY. In some embodiments, the cancer which is deficient in FIR dependent DNA DSB repair comprises one or more cancer cells which have a reduced or abrogated ability to repair DNA DSBs through that pathway, relative to normal cells i.e. the activity of the FIR dependent DNA DSB repair pathway may be reduced or abolished in the one or more cancer cells.

[00235] In some embodiments, the activity of one or more components of the FIR dependent DNA DSB repair pathway is abolished in the one or more cancer cells of an individual having a cancer which is deficient in FIR dependent DNA DSB repair.

[00236] In some embodiments, the cancer cells have a BRCA1 and / or a BRCA2 deficient phenotype i.e. BRCA1 and / or BRCA2 activity is reduced or abolished in the cancer cells. Cancer cells with this phenotype may be deficient in BRCA1 and / or BRCA2, i.e. expression and / or activity of BRCA1 and / or BRCA2 may be reduced or abolished in the cancer cells, for example by means of mutation or polymorphism in the encoding nucleic acid, or by means of amplification, mutation or polymorphism in a gene encoding a regulatory factor, for example the EMSY gene which encodes a BRCA2 regulatory factor. BRCA1 and BRCA2 are known tumor suppressors whose wild-type alleles are frequently lost in tumors of heterozygous carriers. Amplification of the EMSY gene, which encodes a BRCA2 binding factor, is also known to be associated with breast and ovarian cancer. Carriers of mutations in BRCA1 and / or BRCA2 are also at elevated risk of certain cancers, including breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, a hematological cancer, gastrointestinal cancer, and lung cancer.

[00237] Ib minimize the risks of off-target effects, it is desirable for drug molecules to possess selectivity for a. specific target.

[00238] Avoiding inhibition of PARP family isoforms beyond PARPI may be important in minimizing toxicities that may arise from inhibition of non-PARPl isoforms. Ilie pharmacology of inhibiting PARI’ isoforms beyond PARPI may drive toxicities that reduce the therapeutic index for agents that possess lower selectivity’s for PARPI against PARR isoforms. PARP3, like PARPI, plays a role in DNA damage but has also been found to be a key player in the integrity of the mitotic spindle and in telomerase integrity (Boehler, C., Gauthier, LR., Mortusewicz O. et al. Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression. PNAS, January 26, 2011, 108 (7) 2783-2788 ). PARP5A also known as Tankyra.se 1, plays key roles in Wnt signaling and telomere length (Kulak. 0., Chen, H., Holohan B. et al. Disruption of Wnt''P-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Celis. Mol Ceil Biol. 2015 Jul; 35(14), 2425-2435). PARP6 is an essential microtubtde-regulatoty gene in mice, gernihne mutations in PARP6 that abrogate the catalytic activity has negative effects on neuronal function in humans (Vennehren-Schmaedick, A., Huang J.Y., Levinson, M. et al. Characterization of PARP6 Function in Knockout Mice and Patients with Developmental Delay. Cells, 2021 Jun; 10(6), 1289). PARP7 catalytic inhibition causes hyper stimulatory effects on type one interferon producing an autoimmune phenotype (Gozgit, J.M., Vasbinder, M.M., Abo, R.P. et al. PA.RP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity. Volume 39, Issue 9. 13 September 2021, Pages 1214-1226). While the exact function of PARP8 has not been established, its knockout has been shown to induce mitotic and nuclear morphology defects and a decrease tn cellular viability (Vyas, S., Chesarone-Cataldo, M., Todorova, T., et al. A Systematic Analysis of the PARP Protein Family Identifies New Functions Critical for Cell Physiology. Nat. Commun. 2013, 4 (1), 2240). PARP10 has been described as aMYC interacting protein widi tumor suppressor activities (Yu, M., Schreek, S., Cemi, C. et al. PARP-10, a novel Myc-interacting protein with poly(ADP-ribose) polymerase activity, inhibits transfbnnaiion. Oncogene, 2005 volume 24, pagesl.982-1993).

[00239] In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are PARPI selective over other members of the PARP family including PARP2, PARP3, PARP6, PARP7, PARP8, PARP10, PARP11, PARP14, PARP15, TNKS1 (PARP5A), and TNKS2 (PARP5B). In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are selective for PARPl over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are selective for PARPl over PARP3. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are selective for PARPl over PARP6. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are selective for PARP1 over PARP7. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have selective for PARP1 over PARP8. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are selective forPARPl over PARP10. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are selective for PARP1 over PARP11. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are selective for PARPl over PARP14. In some embodiments, tire compounds disclosed herein, or a. pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are selective for PARPl over PARPl 5. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are selective for PARPl over TNKS1 (PARP5A). In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are selective for PARPl over TNKS2 (PARP5B).

[00240] In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more than 10000-fold more PARPl selective over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more than 9000-fold more PARPl selective over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are more than 8000-fold more PARPl selective over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutmally acceptable salt, solvate, or stereoisomer thereof, are more than 7000-fold more PARPl selective over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more than 6000-fold more PARPl selective over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more than 5000-fold more PARP l selective over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more than 4000-fold more PARP l selective over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more than 3000-fold more PARPl selective over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more than 2000-fold more PARPl selective over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more than 1000-fold more PARPl selective over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more than 100-fold more PARPl selective over PARP2. In some embodiments, the compounds disclosed herein has at least a 400- to 600-fold selectivity for PARPl over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 400-fold selectivity for PARPl over PARP2. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 500-fold selectivity for PARPl over PARP2.

[00241] hi some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more than I00-fo1d more PARPl selective over PARP3. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more than 200-fold more PARPl selective over PAR.P3.

[00242] hi some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 200- to 700-fold selectivity for PARPl over PARP3. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 200-fold selectivity for PARPl over PARP3. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 650-fold selectivity for PARPl over PARP3.

[00243] In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have more than 1000-fold more PARPl selective over PARP6. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 2000- to 3000-fold selectivity for PARPl over PARP6. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 2400-fold selectivity for PARPl over PARP6. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 3000-fold selectivity for PARPl over PARP6.

[00244] Tn some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have more than 500-fold more PARPl selective over PARP7. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 600- to 900-fold selectivity for PARPl over PARP7. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 600-fold selectivity for PARPl over PARP7. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 800-fold selectivity for PARPl over PARP7.

[00245] In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have more than 3000-fold more PARPl selective over PARP8. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 5000- to 9000-fold selectivity for PARPl over PARP8. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a. 8000-fo1d selectivity for PARPl over PARP8. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 5000-fold selectivity for PARP1 over PARP8.

[00246] In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have more than 200-fold more PARP1 selective over PARP10. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 300- to 400-fold selectivity for PARI’l over PARP10. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 350-fold selectivity for PARPl over PARP10. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 300-fold selectivity for PARI’l over 1’ARPIO.

[00247] In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have more than 5-fold more PARP1 selective over PARPl1. In some embodiments, die compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 5- to 270-fold selectivity for PARPl over PARPl 1. hi some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a. 6-fold selectivity for PARPl over PARPl I. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 270-fold selectivity for PARPl over PARPl 1.

[00248] In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have more than 2000-fold more PARPl selective over PARP14. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof have at least a 1400- to 2600-fold selectivity for PARPl over PARPl4. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 1400-fold selectivity' for PARPl over PARPl 4. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 2600-fold selectivity for PARPl over PARP14.

[00249] In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have more than 1000-fold more PARPl selective over PARPl 5. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 1600-fold selectivity for PARPl over PARPl 5.

[00250] hi some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have more than 100-fold more PARPl selective over TNKSI (PARP5A). In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 100- to 250-fold selectivity for PARPl over TNKSI (PARP5A). In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a I00-fo1d selectivity for PARPl over TNKSI (PAR.P5A). In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 230-fold selectivity for PARP1 over TNKS1 (PARP5A).

[00251] In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have more than. 100-fold more PARP1 selective over TNKS2 (PA.RP5.B). In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 10()- to 150-fold selectivity for PARP1 over TNKS2 (PARP5B). In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 140-fold selectivity for PARP1 over TNKS'2 (PARP5B). In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have at least a 130-fold selectivity for PARP1 over TNKS2 (PARP5B). Dosing

[00252] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[00253] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient’s state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of or risk factor for the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.

[00254] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[00255] In certain embodiments wherein a patient’s status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[00256] Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent or daily treatment on a longterm basis upon any recurrence of symptoms.

[00257] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[00258] In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[00259] In one embodiment, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg / kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[00260] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LDw and the ED90. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and / or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity. In certain embodiments, the daily dosage range and / or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.

[00261] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and / or (b) administered orally to the mammal; and / or (c) intravenously administered to the mammal; and / or (d) administered by injection to the mammal; and / or (e) administered topically to the mammal; and / or (f) administered non-systemically or locally to the mammal.

[00262] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.

[00263] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the subject every 12 hours; (v) the compound is administered to the subject every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year. Routes of Administration

[00264] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[00265] In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the compound described herein is administered topically. Pharmaceutical Compositions / Formulations

[00266] The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In one embodiment, the compounds of this invention may be administered to animals. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

[00267] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), herein incorporated by reference for such disclosure.

[00268] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, fdling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.

[00269] The pharmaceutical compositions described herein are administered to a subject by appropriate administration routes, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[00270] Pharmaceutical compositions including compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.

[00271] Pharmaceutical compositions for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. In some embodiments, dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[00272] Pharmaceutical compositions that are administered orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added.

[00273] Pharmaceutical compositions for parental use are formulated as infusions or injections. In some embodiments, the pharmaceutical composition suitable for injection or infusion includes sterile aqueous solutions, or dispersions, or sterile powders comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, saline, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and any combinations thereof. In some embodiments, the pharmaceutical compositions further comprise a preservative to prevent growth of microorganisms. Combination

[00274] Disclosed herein are methods of treating cancer using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[00275] In some embodiments, the additional therapeutic agent is an anticancer agent.

[00276] In some embodiments, the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein. EXAMPLES Example 1 Step 1: Preparation of tert-butyl 4-[2-cyano-6-(methylcarbamoyl)pyridin-3-yl]piperazine-l-carboxylate:

[00277] To a stirred solution of tert-butyl 4-[2-bromo-6-(methylcarbamoyl)pyridin-3-yl]piperazine-l-carboxylate (1.00 g, 2.50 mmol, 1.00 equiv.) and Zn(CN)2 (0.44 g, 3.76 mmol, 1.50 equiv.) in DMF (10 mL) were added Pd(PPh3)4 (0.29 g, 0.25 mmol, 0.10 equiv.) at room temperature under N2 atmosphere. The resulting mixture was stirred for 3h at 120°C under N2 atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with H2O (50 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The pure fraction was concentrated under vacuum to afford tert-butyl 4-[2-cyano-6-(methylcarbamoyl)pyridin-3-yl]piperazine-l-carboxylate (460 mg, 53.1%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =346.2. 1HNMR (300 MHz, DMSO-d6) 5 8.60 (q, 1H), 8.13 (d, 1H), 7.76 (d, 1H), 3.52 (dd, 4H), 3.33 (d, 4H), 2.80 (d, 3H), 1.43 (s, 9H). Step 2: Preparation of 6-cyano-N-methyl-5-(piperazin-l-yl)pyridine-2-carboxamide, HC1 salt:

[00278] To a stirred solution of tert-butyl 4-[2-cyano-6-(methylcarbamoyl)pyridin-3-yl]piperazine-l-carboxylate (260 mg, 0.75 mmol, 1.00 equiv.) in dioxane (2 ml) was added HC1 (gas) in 1,4-dioxane (2 mL, 4M in 1,4-dioxane) dropwise at ice bath. The resulting mixture was stirred for Ih at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to afford 6-cyano-N-methyl-5-(piperazin-l-yl)pyridine-2-carboxamide, HC1 salt (180 mg, 97.4%) The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m / z)-. [M+H]+ =245.9. 1HNMR (300 MHz, DMSO-d6) 5 9.32 (brs, 2H), 8.65 (d, 1H), 8.16 (d, 1H), 7.86 (d, 1H), 3.58 (dd, 4H), 3.29 (s, 4H), 2.80 (d, 3H). Step 3: Preparation of 6-cyano-5-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl}-N-methylpyridine-2-carboxamide: To a stirred solution of 7-(chloromethyl)-3-ethyl-lH-l,5-naphthyridin-2-one (50 mg, 0.22 mmol, 1.00 equiv.) and 6-cyano-N-methyl-5-(piperazin-l-yl)pyridine-2-carboxamide (60 mg, 0.25 mmol, 1.10 equiv.) and KI (7 mg, 0.04 mmol, 0.20 equiv.) in MeCN (3 mL) were added DIEA (145 mg, 1.12 mmol, 5.00 equiv.) dropwise at room temperature under N2 atmosphere. The resulting mixture was stirred for 2h at 80°C under N2 atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (3 mL).The crude product was purified by Prep-HPLC. The pure fraction was concentrated and lyophilized to afford 6-cyano-5-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl}-N-methylpyridine-2-carboxamide (12.9 mg, 13.11%) as a white solid. LC-MS: (ES+H, Wz): [M+H]+=431.9. lHNMR(300 MHz, DMSO-d6) 5 11.87 (s, 1H), 8.58 (d, 1H), 8.42 (s, 1H), 8.11 (d, 1H), 7.74 (d, 2H), 7.62 (s, 1H), 3.68 (s, 2H), 3.37 (d, 4H), 2.79 (d, 3H), 2.60-2.56 (m, 6H), 1.19 (t, 3H). The following examples were made using similar procedures shown for example 1. Ex NMR LCMS (ESI) m / z 37 1HNMR(400 MHz, DMSO-d6) 5 11.88 (s, 1H), 8.57 (q, 1H), 8.41 (d, 1H), 8.11 (d, 1H), 7.83 (s, 1H), 7.74 (d, 1H), 7.62 (d, 1H), 3.68 (s, 2H), 3.37 (m, 4H), 2.79 (d, 3H), 2.61 (m, 4H), 2.14 (d, 3H). [M+H]+=418.25 97 1HNMR(300 MHz, DMSO-d6) 5 11.90 (s, 1H), 8.58 (d, 1H), 8.40 (d, 1H), 8.11 (d, 1H), 7.75 (d, 1H), 7.60 (s, 1H), 7.43 (s, 1H), 3.67 (s, 2H), 3.41 - 3.35 (m, 4H), 2.79 (d, 3H), 2.61 (t, 4H), 2.18 - 2.11 (m, 1H), 1.03 - 0.93 (m, 2H), 0.84-0.81 (m, 2H). [M+H]+=444.2 Example 2 5 Step 1: Preparation of tert-butyl (3R)-4-[6-(methoxycarbonyl)pyridin-3-yl]-3-methylpiperazine-l-carboxylate:

[00279] A mixture of tert-butyl (3 R)-3-methylpiperazine-1-carboxylate (5.00 g, 24.96 mmol, 1.00 equiv, [a]26D (c = 1.0, CHCL): +14.75), methyl 5-bromopyridine-2-carboxylate (5.66 g, 26.21 mmol, 1.05 equiv), CS2CO3 (16.27 g, 49.93 mmol, 2.00 equiv) and RuPhos Palladacycle Gen.3 (1.04 g, 1.25 mmol, 0.05 equiv) in 1,4-dioxane (50 mL) was stirred overnight at 120°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (100 mL), and then was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl (3R)-4-[6-(methoxycarbonyl)pyridin-3-yl]-3-methylpiperazine-l-carboxylate (5.00 g, 59.71%) as a white solid. LC-MS: (ES+H, m / zy [M+H]+ =336.1. Step 2: Preparation of tert-butyl (3R)-3-methyl-4-[6-(methylcarbamoyl)pyridin-3-yl]piperazine-l-carboxylate:

[00280] A solution of tert-butyl (3R)-4-[6-(methoxycarbonyl)pyridin-3-yl]-3-methylpiperazine-l-carboxylate (2.00 g, 5.96 mmol, 1.00 equiv) and methanamine (8 mL, 25-30 wt% solution in water) in CH3OH (7 mL) was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with sat. NH4CI (30 mL) at room temperature. The resulting mixture was extracted with CH2CI2 (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl (3R)-3-methyl-4-[6-(methylcarbamoyl)pyridin-3-yl]piperazine-l-carboxylate (1.70 g, 85.25%) as a light yellow oil. LC-MS: (ES+H, m / zy [M+H]+ =335.3. Step 3: Preparation of N-methyl-5-[(2R)-2-methylpiperazin-l-yl]pyridine-2-carboxamide, HC1 salt:

[00281] A mixture of tert-butyl (3R)-3-methyl-4-[6-(methylcarbamoyl)pyridin-3-yl]piperazine-l-carboxylate (500 mg, 1.50 mmol, 1.00 equiv) and HC1 (gas) in 1,4-dioxane (3.7 mL, 14.95 mmol, 10.00 equiv, 4.0 M) was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to afford N-methyl-5-[(2R)-2-methylpiperazin-l-yl]pyridine-2-carboxamide, HC1 salt (400 mg, crude) as a yellow solid. The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m / zy. [M+H]+ =234.9. Step 4: Preparation of 5-[(2R)-4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]-2-methylpiperazin-l-yl]-N-methylpyridine-2-carboxamide:

[00282] A mixture ofN-methyl-5-[(2R)-2-methylpiperazin-l-yl]pyridine-2-carboxamide, HC1 salt (128 mg, crude), 7-(chloromethyl)-3-ethyl-lH-l,5-naphthyridin-2-one (100 mg, 0.45 mmol, 1.00 equiv) and KI (15 mg, 0.09 mmol, 0.20 equiv) and DIEA (290 mg, 2.24 mmol, 5.00 equiv) in MeCN (10 mL) was stirred for 3 h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (2x30 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford a crude product. The crude product was further purified by Prep-HPLC. The pure fraction was concentrated under reduced pressure and lyophilized to afford 5-[(2R)-4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]-2-methylpiperazin-l-yl]-N-methylpyridine-2-carboxamide (90 mg, 46.89%) as a white solid. LC-MS: (ES+H, Wz): [M+H]+=421.2. Tf NMR (400 MHz, DMSO-J6) 5 11.90 (s, 1H), 8.42 (d, 1H), 8.37 (d, 1H), 8.21 (d, 1H), 7.82 (d, 1H), 7.76 (s, 1H), 7.67 (d, 1H), 7.33 (dd, 1H), 4.23 (s, 1H), 3.71 (d, 1H), 3.65 - 3.52 (m, 2H), 3.14 - 3.03 (m, 1H), 2.93 (d, 1H), 2.78 (d, 3H), 2.72 (d, 1H), 2.58 - 2.53 (m, 2H), 2.33 (dd, 1H), 2.29 - 2.15 (m, 1H), 1.19 (t, 3H), 1.13 (d, 3H). The following examples were made using similar procedures shown for example 2. Ex NMR LCMS (ESI) m / z 27 'HNMR (300 MHz, DMSO-d6) 5 11.91 (s, 1H), 8.42 (d, 1H), 8.38 (d, 1H), 8.21 (d, 1H), 7.83 (d, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.33 (dd, 1H), 4.22 (brs, 1H), 3.72 (d, 1H), 3.65 - 3.53 (m, 2H), 3.15-3.03 (m, 1H), 2.94 (d, 1H), 2.78 (d, 3H), 2.72 (d, 1H), 2.60 - 2.53 (m, 2H), 2.34-2.22 (m, 2H), 1.26 - 1.04 (m, 6H). [M+H]+=420.95 30 'HNMR (300 MHz, DMSO-J6) 5 11.85 (s, 1H), 8.43 - 8.35 (m, 2H), 7.75 (s, 1H), 7.62 (d, 1H), 7.13 (s, 1H), 3.66 (s, 2H), 3.24-3.20 (m, 4H), 2.74 (d, 3H), 2.61-2.52 (m, 6H), 1.19 (t, 3H). [M+H]+=413.25 33 'HNMR (400 MHz, DMSO-d6) 5 11.87 (s, 1H), 8.44 - 8.36 (m, 2H), 8.27 (d, 1H), 7.85 - 7.80 (m, 2H), 7.62 (s, 1H), 7.39 (dd, 1H), 3.65 (s, 2H), 2.56 (t, 4H), 2.78 (d, 3H), 2.56 (t, 4H), 2.14 (d, 3H). [M+H]+=393.2 34 1H NMR (300 MHz, DMSO-d6): 5 11.89 (s, 1H), 8.45 - 8.36 (m, 2H), 7.84 (dd, J = 8.0, 1.5 Hz, 1H), 7.62 -7.52 (m, 2H), 7.42 (s, 1H), 3.64 (s, 2H), 3.31 -3.13 (m, 4H), 2.76 (d, J = 4.8 Hz, 3H), 2.61-2.53 (m, 4H), 2.20 - 2.07 (m, 1H), 1.03 - 0.91 (m, 2H), 0.87 - 0.75 (m, 2H). 19F NMR (282 MHz, DMSO-d6) 5 -72.53. [M+H]+=437. 15. 35 'HNMR (300 MHz, DMSO-d6) 5 11.87 (s, 1H), 8.41 (d, 1H), 8.27 (q, 1H), 8.13 (s, 1H), 7.76 (s, 1H), 7.62 (d, 1H), 7.22 (dd, 1H), 3.39 (m, 4H), 2.75 (d, 3H), 2.60 - 2.52 (m, 6H), 1.19 (t, 3H). 19F NMR (282 MHz, DMSO) 5-120.39. [M+H]+=427.15 38 'HNMR (300 MHz, DMSO-d6) 5 11.88 (s, 1H), 8.47- 8.45(m, 2H), 8.12 (d, 1H), 8.03 (q, 1H), 7.84 (s, 1H), 7.62 (s, 1H), 7.20 (d, 1H), 3.68 (s, 2H), 3.343.29 (m, 4H), 2.77 (s, 3H), 2.66-2.58 (m, 4H), 2.15 (s, 3H). [M+H]+=417.25 39 'HNMR (300 MHz, DMSO-d6, D2O exchange) 58.41 (s, 1H), 8.18 (br s), 8.02 (s, 1H), 7.78 (s, 1H), 7.73 (s, 1H), 7.04 (dd, 1H), 4.23 - 4.08 (m, 1H), 3.71 (d, 1H), 3.56 (d, 2H), 3.16 - 3.05 (m, 1H), 2.95 - 2.82 (m, 1H), 2.73 - 2.64 (m, 4H), 2.57 - 2.50 (m, 2H), 2.35- 2.11 (m, 2H), 1.22 - 1.05 (m, 6H). 19F NMR (282 MHz, DMSO) 5 -120.36. [M+H]+=43 9.1 51 'HNMR(400 MHz, DMSO-d6) 5 11.93 (s, 1H), 8.45 - 8.41 (m, 2H), 7.92 (s, 1H), 7.77 (s, 1H), 7.66 (s, 1H), 6.75 (d, 1H), 4.81 - 3.41 (m, 6H), 2.75 (d, 3H), 2.61 - 2.50 (m, 6H), 1.19 (t, 3H). 19F NMR (282 MHz, DMSO) 5 -73.47. [M+H]+=425.2 61 'HNMR (300 MHz, DMSO-d6) 5 11.85 (s, 1H), 8.78 (d, 1H), 8.41 (d, 1H), 7.83 (d, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.34 (d, 1H), 3.73 - 3.69 (m, 4H), 3.66 (s, 2H), 2.81 (d, 3H), 2.58 - 2.52 (m, 6H), 1.18 (t, 3H). [M+H]+=408.15 63 'HNMR (400 MHz, DMSO-d6) 5 11.88 (s, 1H), 8.42-8.33 (m, 2H), 8.23 (d, 1H), 7.85-7.80 (m, 2H), 7.62 (s, 1H), 7.39 (dd, 1H), 3.65(s, 2H), 3.34-3.31 (m, 4H), 2.89-2.80 (m, 1H), 2.55 (m, 4H), 2.14 (s 3H), 0.70-0.58 (m, 4H). [M+H]+=419.10 Ex NMR LCMS (ESI) m / z 66 'HNMR (300 MHz, DMS0-d6) 5 11.91 (s, 1H), 8.60 (d, 1H), 8.41 (d, 1H), 8.12 (d, 1H), 7.86 - 7.78 (m, 2H), 7.65 (s, 1H), 4.02 (s, 1H), 3.65 (q, 2H), 3.47 (m, 1H), 3.22 (m, 1H), 2.90 - 2.76 (m, 4H), 2.55 (m, 2H), 2.42 (m, 1H), 2.14 (d, 3H), 1.13 (d, 3H). [M+H]+=432.2 67 'HNMR (300 MHz, DMS0-d6) 5 11.89 (s, 1H), 8.38 - 8.22 (m, 3H), 7.83 (d, 1H), 7.61 (s, 1H), 7.39 (m, 2H), 3.64 (s, 2H),3.32 - 3.24 (m, 4H), 2.53 - 2.43 (m, 4H), 2.25 - 2.10 (m, 1H),1.O8 - 0.90 (m, 2H), 0.89 - 0.73 (m, 2H). [M+H]+=422.2 68 'HNMR (400 MHz, DMS0-d6) 5 11.88 (s, 1H), 8.44 - 8.33 (m, 2H), 8.27 (d, 1H), 7.81 (d, 1H), 7.76 (s, 1H), 7.64 (d, 1H), 7.39 (dd, 1H), 4.77 (dd, 1H), 4.65 (dd, lH),4.51(s, 1H), 3.76-3.63 (m, 2H), 3.59 (d, 1H), 3.26 - 3.14 (m, 1H), 2.92 (t, 2H), 2.78 (d, 3H), 2.59 - 2.53 (m, 2H), 2.38 - 2.15 (m, 2H), 1.19 (t, 3H). 19F NMR (377 MHz, DMSO) 8-223.51. [M+H]+=439.15 74 'HNMR (400 MHz, DMS0-d6) 8 11.94 (s, 1H), 8.41 - 8.35 (m, 2H), 8.20 (d, 1H), 7.82 (d, 1H), 7.65 (s, 1H), 7.42 (s, 1H), 7.33 (dd, 1H), 4.26 - 4.17 (m, 1H), 3.70 (d, 1H), 3.64-3.51 (m, 2H), 3.08 (td, 1H), 2.93 (d, 1H), 2.78 (d, 3H), 2.71 (d, 1H), 2.32 (dd, 1H), 2.28 - 2.09 (m, 2H), 1.12 (d, 3H), 1.01-0.93 (m, 2H), 0.85 - 0.78 (m, 2H). [M+H]+=433.30 79 'HNMR (400 MHz, DMSO-d6) 8 11.91 (s, 1H), 9.06 (d, 1H), 8.42 (d, 1H), 8.24 (d, 1H), 7.82 (d, 1H), 7.76 (s, 1H), 7.70-7.65 (m, 1H), 7.34 (dd, 1H), 5.08-4.95 (m, 1H), 4.75-4.68 (m, 4H), 4.30-4.24 (m, 1H), 3.75-3.54 (m, 3H), 3.14-3.04 (m, 1H), 2.95-2.92 (m, 1H), 2.74-2.71(m, 1H), 2.58-2.53 (m, 2H), 2.37-2.19 (m, 2H), 1.26-1.11 (m, 6H). [M+H]+=463.10 93 'HNMR (300 MHz, DMSO-d6) 8 11.90 (s, 1H), 8.57 (s, 1H), 8.42 (d, 1H), 8.12 (d, 1H), 7.85 - 7.72 (m, 2H), 7.65 (d, 1H), 4.09 - 3.94 (m, 1H), 3.76 -3.55 (m, 2H), 3.43-3.23 (m, 2H), 2.78 (m, 1H), 2.60 - 2.52 (m, 4H), 2.42 (t, 1H), 1.24- 1.09 (m, 6H). [M+H]+=449.2 100 'HNMR(300 MHz, DMSO-d6) 8 11.88 (s, 1H), 8.38 (d, 1H), 8.26 (dd, 1H), 8.12 (s, 1H), 7.60 (d, 1H), 7.42 (s, 1H), 7.21 (dd, 1H), 3.63 (s, 2H), 3.41-3.35 (m, 4H), 2.74 (d, 3H), 2.56-2.52 (m, 4H), 2.19-2.09 (m, 1H), 1.01-0.94 (m, 2H), 0.85-0.79 (m, 2H). 19F NMR (282 MHz, DMSO) 8 -120.40. [M+H]+=437.25 105 'HNMR (300 MHz, DMSO-d6) 8 11.86 (s, 1H), 8.40 (d, 1H), 8.25 (d, 1H), 8.11 (s, 1H), 7.76 (s, 1H), 7.62 (d, 1H), 7.22 (dd, 1H), 3.65 (s, 2H), 3.41-3.35 (m, 4H), 2.85 - 2.74 (m, 1H), 2.60 - 2.52 (m, 6H), 1.19 (t, 3H), 0.72-0.62 (m, 2H), 0.54-0.61 (m, 2H). 19F NMR (282 MHz, DMSO) 8 -120.46 [M+H]+=451.4 108 'HNMR (400 MHz, DMSO-d6) 8 11.88 (s, 1H), 8.39 (d, 1H), 8.25 (d, 1H), 8.10 (t, 1H), 7.83 (d, 1H), 7.61 (d, 1H), 7.22 (dd, 1H), 3.65 (s, 2H), 3.41-3.34 (m, 4H), 2.86-2.74 (m, 1H), 2.57-2.5 l(m, 4H), 2.14 (d, 3H), 0.70-0.63 (m, 2H), 0.61-0.54 (m, 2H). 19F NMR (282 MHz, DMSO) 8-120.46. [M+H]+=437.20 115 'HNMR (300 MHz, DMSO-d6) 8 8.39 (d, 2H), 8.25 (s, 1H), 7.83 (d, 1H), 7.61 (s, 1H), 7.46-7.26 (m, 2H), 3.51-3.32 (m, 4H), 2.78 (d, 3H), 2.78-2.54 (m,4H),2.14-2.13 (m,lH), 0.97-0.96 (m, 2H), 0.87-0.76 (m, 2H). [M+H]+=421.2 116 'HNMR (400 MHz, DMSO-d6) 8 11.89 (s, 1H), 8.38-8.36 (m, 2H), 8.26 (d, 1H), 7.83 (d, 1H), 7.60 (d, 1H), 7.44-7.35 (m, 2H), 3.36-3.30 (m, 4H), 2.552.53 (m, 4H), 2.15-2.13 (m, 1H), 1.00-0.94 (m, 2H), 0.86-0.78 (m, 2H) [M+H]+=424.25 117 'HNMR(400 MHz, DMSO-d6) 8 11.90 (s, 1H), 8.37 (dd, 2H), 8.23 (d, 1H), 7.83 (d, 1H), 7.60 (d, 1H), 7.45 -7.35 (m, 2H), 3.33-3.26 (m, 4H), 2.90-2.80 (m, 1H), 2.61-2.52 (m, 4H), 2.20-2.09 (m, 1H), 1.04-0.91 (m, 2H), 0.88-0.77 (m, 2H), 0.70-0.56 (m, 4H). [M+H]+=447.30 Ex NMR LCMS (ESI) m / z 119 1HNMR(400 MHz, DMSO-d6) 5 11.88 (s, 1H), 8.39 (d, 2H), 8.26 (d, 1H), 7.83 (d, 1H), 7.61 (d, 1H), 7.45 - 7.34 (m, 2H), 3.64 (s, 2H), 3.41 - 3.32 (m, 4H), 2.59 - 2.52 (m, 4H), 2.19 - 2.10 (m, 1H), 1.01 - 0.93 (m, 2H), 0.85 -0.79 (m, 2H). [M+H]+=438.15. 134 XH NMR (300 MHz, DMSO-d6) 5 11.86 (s, 1H), 8.40 (d, 1H), 7.85 (t, 1H), 7.76 (s, 1H), 7.62 (d, 1H), 7.48 (t, 1H), 6.81 - 6.69 (m, 2H), 3.64 (s, 2H), 3.28 (d, 4H), 2.80 (tt, 1H), 2.56 (dd, 6H), 1.19 (t, 3H), 0.66 (td, 2H), 0.56 - 0.49 (m, 2H). 19F NMR (282 MHz, DMSO) 5-111.70. [M+H]+=450.15 137 XH NMR (300 MHz, DMSO-d6) 5 11.88 (s, 1H), 8.43 - 8.39 (m, 2H), 8.26 (d, 1H), 7.83 (d, 1H), 7.61 (d, 1H), 7.42 - 7.37 (m, 2H), 3.64 (s, 2H), 3.33 - 3.29 (m, 2H), 3.27 - 3.24 (m, 4H), 2.56 (s, 4H), 2.20 - 2.10 (m, 1H), 1.10 (t, 3H), 1.00 - 0.94 (m, 2H), 0.85 (d, 2H). [M+H]+=433.15 139 XH NMR (300 MHz, DMSO-d6) 5 11.86 (s, 1H), 8.55 (d, 1H), 8.42 (d, 1H), 8.10 (d, 1H), 7.74 (d, 2H), 7.62 (d, 1H), 3.69 (s, 2H), 3.42 - 3.33 (m, 4H) 2.932.81 (m, 1H), 2.64-2.5 l(m,6H), 1.19 (t, 3H), 0.73 - 0.64 (m, 4H). [M+H]+=458.20 145 XH NMR (300 MHz, DMSO-d6) 5 11.86 (s, 1H), 8.45 - 8.36 (m, 1H), 8.18 (s, 1H), 7.89 - 7.74 (m, 2H), 7.62 (s, 1H), 7.00 (d, J = 8.9 Hz, 1H), 3.67 (s, 2H), 3.36-3.33 (m, 4H), 2.77 (d, J = 4.5 Hz, 3H), 2.58-2.50 (m, 6H), 1.19 (t, J = 7.4 Hz, 3H). 19F NMR (282 MHz, DMSO) 5 -106.65. [M+H]+=449.10 158 XH NMR (300 MHz, DMSO-d6) 5 11.90 (s, 1H), 8.40-8.33 (m, 2H), 7.84 (d, J = 7.9 Hz, 1H), 7.63 -7.51 (m, 2H), 7.42 (s, 1H), 3.64 (s, 2H), 3.19 - 3.14 (m, 4H), 2.87 - 2.84 (m, 1H), 2.59 - 2.54 (m, 4H), 2.17 - 2.14 (m, 1H), 0.99 -0.95 (m, 2H), 0.86 - 0.77 (m, 2H), 0.69 - 0.62 (m, 4H). 19F NMR (282 MHz, DMSO) 5 -72.41. [M+H]+=463.20 161 1H NMR (300 MHz, DMSO-d6) 5 11.82 (s, 1H), 8.40-8.37 (m, 2H), 8.27 (d, 1H), 7.82 (d, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.39 (dd, 1H), 4.11 (d, 1H), 3.71 (d, 1H), 3.60 (d, 1H), 3.41 - 3.36 (m, 1H) 2.96 (t, 1H), 2.84 - 2.70 (m, 5H), 2.64 - 2.53 (m, 3H), 2.28 (t, 1H), 1.25 - 1.09 (m, 6H). [M+H]+ =420.90 Examples 3A and 3B Step 1: Preparation of tert-butyl 5-[6-(methoxycarbonyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate:

[00283] To a stirred mixture of methyl 5-bromopyridine-2-carboxylate (2.5 g, 11.57 mmol, 1 equiv) and tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (2.41 g, 12.15 mmol, 1.05 equiv) in dioxane (25 ml) were added RuPhos Palladacycle Gen.3 (0.48 g, 0.57 mmol, 0.05 equiv) and CS2CO3 (7.54 g, 23.14 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 110 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with sat. NaCl( aq) (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 5-[6-(methoxycarbonyl)pyridin-3-yl]-2,5-diazabicyclo[4.1,0]heptane-2-carboxylate (1.1g, Y=28.4%) as ayellow solid. LC-MS: (ES+H, m / z): [M+H]+ =334.1 Step 2: Preparation of tert-butyl 5-[6-(methylcarbamoyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate:

[00284] A mixture of tert-butyl 5-[6-(methoxycarbonyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (1 g, 3.00 mmol, 1 equiv) and CH3NH2 (2.33 g, 75.03 mmol, 25.01 equiv 40% in H2O) in MeOH (15 ml) was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (40 mL). The mixture was acidified to pH 6 with saturated NH4CI (aq.). The resulting mixture was extracted with CH2Q2 (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 5-[6-(methylcarbamoyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0] heptane-2-carboxylate (1.2 g, crude) as ayellow crude oil. LC-MS: (ES+H, m / z): [M+H]+=333.1 Step 3: Preparation of 5-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-N-methylpyridine-2-carboxamide:

[00285] To a stirred mixture of tert-butyl 5-[6-(methylcarbamoyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (1.2 g, 3.61 mmol, 1 equiv) in MeOH (10 ml) was added HCl(gas)in 1,4-dioxane (6 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with diethyl ether (40 mL). The resulting mixture was concentrated under reduced pressure to afford 5-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-N-methylpyridine-2-carboxamide (1 g, crude) as ayellow crude oil. LC-MS: (ES+H, m / z): [M+H]+ =232.9 Step 4: Preparation of 5-{5-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl}-N-methylpyridine-2-carboxamide:

[00286] To a stirred mixture of 5-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-N-methylpyridine-2-carboxamide (547.67 mg, 2.35 mmol, 1.5 equiv) and 7-(chloromethyl)-3-ethyl-lH-l,5-naphthyridin-2-one (350 mg, 1.57 mmol, 1.00 equiv) in acetonitrile (5 ml) were added KI (52.19 mg, 0.31 mmol, 0.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 5-{5-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl}-N-methylpyridine-2-carboxamide (180 mg, Y=21.3%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =419.0 Step 5: Preparation of rel-5-[(lR,6S)-5-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-N-methylpyridine-2-carboxamide (Example 3A) and rel-5-[(lR,6S)-5-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-N-methylpyridine-2-carboxamide (Example 3B) :

[00287] rel-5-[(lR,6S)-5-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]-2,5- diazabicyclo[4.1.0]heptan-2-yl]-N-methylpyridine-2-carboxamide was purified by PREPCHIRALHPLC to afford rel-5-[(lR,6S)-5-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-N-methylpyridine-2-carboxamide (Example 3A, 54.8mg, Y=30.4%, ee=99.28%) and rel-5-[(lR,6S)-5-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-N-methylpyridine-2-carboxamide (Example 3B, 39.0 mg , Y=21.6%, ee =98.42%). Note: The stereochemical assignments of examples 3A and 3B are arbitrary. Example 3A:

[00288] LC-MS: (ES+H, m / z): [M+H]+ =419.2. 1HNMR(4OO MHz, DMSO-d6) 5 11.83 (s, 1H), 8.44 (d, 1H), 8.37 - 8.32 (m, 1H), 8.19 (d, 1H), 7.85 (d, 1H), 7.75 (s, 1H), 7.69 - 7.65 (m, 1H), 7.27 (dd, 1H), 3.89 (q, 2H), 3.54 - 3.46 (m, 1H), 3.24 - 3.16 (m, 1H), 2.81 - 2.69 (m, 5H), 2.57 - 2.52 (m, 4H), 1.18 (t, 3H), 0.83 - 0.74 (m, 1H), 0.44 - 0.34 (m, 1H). Example 3B:

[00289] LC-MS: (ES+H, m / z): [M+H]+ =419.1. 1HNMR(4OO MHz, DMSO-d6) 5 11.83 (s, 1H), 8.46 -8.40 (m, 1H), 8.38 - 8.31 (m, 1H), 8.19 (d, 1H), 7.85 (d, 1H), 7.75 (s, 1H), 7.67 (s, 1H), 7.27 (dd, 1H), 3.99 - 3.81 (m, 2H), 3.56 - 3.47 (m, 1H), 3.24 - 3.18 (m, 1H), 2.85 - 2.70 (m, 5H), 2.58 - 2.52 (m, 4H), 1.18 (t, 3H), 0.83 - 0.74 (m, 1H), 0.44 - 0.34 (m, 1H). The following examples in Table 3 were made using similar procedures shown for example 3A and 3B. Table 3: Ex NMR LCMS (ESI) m / z 28 1HNMR(400 MHz, DMSO-r / 6) 5 11.83 (s, 1H), 8.43 (d, 1H), 8.35 (d, 1H), 8.19 (d, 1H), 7.85 (d, 1H), 7.75 (s, 1H), 7.66 (s, 1H), 7.27 (dd, 1H), 3.99 - 3.80 (m, 2H), 3.60 - 3.45 (m, 1H), 3.27-3.14 (m, 1H), 2.84 - 2.75 (m, 4H), 2.74 -2.66 (m, 1H), 2.59-2.52 (m, 4H), 1.18 (t 3H), 0.84 - 0.69 (m, 1H), 0.490.28 (m, 1H). [M+H]+=419.2 69 Tf NMR (300 MHz, DMSO-d6) 5 11.84 (s, 1H), 8.43 (d, 1H), 8.25 (q, 1H), 8.06 (t, 1H), 7.75 (q, 1H), 7.66 (d, 1H), 7.05 (dd, 1H), 3.97 - 3.80 (m, 2H), 3.60-3.45 (m, 1H), 3.26 - 3.15 (m, 1H), 2.83 - 2.69 (m, 5H), 2.57-2.52 (m, 4H), 1.18 (t, 3H), 0.79 (q, 1H), 0.41 (q, 1H). 19F NMR (282 MHz, DMSO) 5 -120.44. [M+H]+=437.20. Ex NMR LCMS (ESI) m / z 88 'HNMR (400 MHz, DMS0-d6) 5 11.83 (s, 1H), 9.04 (d, 1H), 8.44 (d, 1H), 8.23 (d, 1H), 7.84 (d, 1H), 7.75 (s, 1H), 7.66 (d, 1H), 7.28 (dd, 1H), 5.01 (q, 1H), 4.79 - 4.57 (m, 4H), 3.97 - 3.81 (m, 2H), 3.56 - 3.47 (m, 1H), 3.27 -3.19 (m, 1H), 2.84 - 2.70 (m, 2H), 2.58 - 2.52 (m, 4H), 1.18 (t, 3H), 0.78 (q, 1H), 0.38 (q, 1H). [M+H]+=461.2 90 'HNMR (400 MHz, DMS0-d6) 5 11.83 (s, 1H), 8.44 (d, 1H), 8.33 (s, 1H), 8.19 (d, 1H), 7.85 (d, 1H), 7.76 (q, 1H), 7.69 - 7.64 (m, 1H), 7.27 (dd, 1H), 3.88 (q, 2H), 3.56 - 3.48 (m, 1H), 3.25 - 3.17 (m, 1H), 2.85 - 2.67 (m, 2H), 2.58 - 2.52 (m, 4H), 1.18 (t, 3H), 0.78 (q, 1H), 0.39 (q, 1H). [M+H]+=422.1 96 'HNMR (400 MHz, DMSO-d6) 5 11.83 (s, 1H), 8.44 (d, 1H), 8.33 (s, 1H), 8.19 (d, 1H), 7.85 (d, 1H), 7.76 (q, 1H), 7.69 - 7.64 (m, 1H), 7.27 (dd, 1H), 3.88 (q, 2H), 3.56 - 3.48 (m, 1H), 3.25 - 3.17 (m, 1H), 2.85 - 2.67 (m, 2H), 2.58 - 2.52 (m, 4H), 1.18 (t, 3H), 0.78 (q, 1H), 0.39 (q, 1H). [M+H] +=422.3 99 'HNMR (300 MHz, DMSO-d6) 5 11.92 (s, 1H), 8.55 - 8.37 (m, 2H), 8.26 (d, 1H), 7.98 - 7.88 (m, 2H), 7.66 (s, 1H), 7.34 (dd, 1H), 4.05 - 3.86 (m, 2H), 3.66-3.51 (m, 1H), 3.29 (td, 1H), 2.95 - 2.72 (m, 5H), 2.67-2.60 (m, 2H), 2.21 (d, 3H), 0.84 (q, 1H), 0.46 (q, 1H). [M+H]+=405.35 107 'HNMR (300 MHz, DMSO-d6) 5 11.86 (s, 1H), 8.41 (d, 1H), 8.33 (s, 1H), 8.19 (d, 1H), 7.85 (d, 1H), 7.65 (d, 1H), 7.42 (s, 1H), 7.27 (dd, 1H), 3.96 -3.80 (m, 2H), 3.51 (dd, 1H), 3.27 - 3.16 (m, 1H), 2.84 - 2.67 (m, 2H), 2.592.52 (m, 2H),2.16-2.11(m, 1H), 1.02-0.91 (m, 2H), 0.89-0.75 (m, 3H), 0.38 (q, 1H). [M+H]+=434.25 109 'HNMR (300 MHz, DMSO-d6) 5 11.85 (s, 1H), 8.43 (d, 1H), 8.30 (d, 1H), 8.17 (d, 1H), 7.89-7.81 (m, 2H), 7.66 (d, 1H), 7.28 (dd, 1H), 3.98-3.81 (m, 2H), 3.57 - 3.44 (m, 1H), 3.28 - 3.16 (m, 1H), 2.89 - 2.68 (m, 3H), 2.60 -2.49 (m, 2H), 2.14 (s, 3H), 0.77 (q, 1H), 0.70 - 0.59 (m, 4H), 0.38 (q, 1H). [M+H]+=431.10 110 'HNMR (400 MHz, DMSO-d6) 5 11.85 (s, 1H), 8.41 (d, 1H), 8.34 (q, 1H), 8.18 (d, 1H), 7.85 (d, 1H), 7.64 (d, 1H), 7.42 (s, 1H), 7.27 (dd, 1H), 3.94 - 3.80 (m, 2H), 3.50 (td, 1H), 3.25 - 3.17 (m, 1H), 2.81 - 2.68 (m, 5H), 2.57 - 2.51 (m, 2H),2.14(tt, 1H), 1.00-0.91 (m, 2H), 0.86 - 0.73 (m, 3H), 0.38 (q, 1H). [M+H]+=431.25 111 'HNMR (300 MHz, DMSO-d6) 5 11.83 (s, 1H), 8.43 (d, 1H), 8.29 (d, 1H), 8.16 (d, 1H), 7.85 (d, 1H), 7.75 (s, 1H), 7.66 (s, 1H), 7.27-7.24 (m, 1H), 3.99 -3.78 (m, 2H), 3.57 - 3.42 (m, 1H), 3.27 - 3.13 (m, 1H), 2.91 - 2.64 (m, 3H), 2.57-2.51 (m, 4H), 1.18 (t, 3H), 0.83 - 0.55 (m, 5H), 0.37 (q, 1H). [M+H]+=445.15 112 'HNMR (400 MHz, DMSO-d6) 5 11.86 (s, 1H), 8.41 (d, 1H), 8.30 (d, 1H), 8.16 (d, 1H), 7.85 (d, 1H), 7.64 (d, 1H), 7.42 (s, 1H), 7.27 (dd, 1H), 3.95 -3.77 (m, 2H), 3.53-3.43 (m, 1H), 3.25-3.14 (m, 1H), 2.90 - 2.64 (m, 3H), 2.582.52 (m, 2H), 2.19-2.08 (m, 1H), 1.04 - 0.92 (m, 2H), 0.86 - 0.57 (m, 7H), 0.36 (q, 1H). [M+H]+=457.25 113 'HNMR(400 MHz, DMSO-d6) 5 11.85 (s, 1H), 8.41 (d, 1H), 8.24 (q, 1H), 8.06 - 8.05(m, 1H), 7.63 (d, 1H), 7.42 (s, 1H), 7.04 (dd, 1H), 4.02 - 3.76 (m, 2H), 3.59 - 3.43 (m, 1H), 3.24-3.15 (m, 1H), 3.06-2.63 (m,5H), 2.59 - 2.51 (m, 2H), 2.21-2.11 (m, 1H), 1.02-0.91 (m, 2H), 0.87 - 0.74 (m, 3H), 0.40 (q, 1H). 19F NMR (282 MHz, DMSO-d6) 5 -120.45. [M+H]+=449.20 Example 4 Example 4 Step 1: Preparation of tert-butyl (3R)-4-[2-bromo-6-(methylcarbamoyl)pyridin-3-yl]-3-methylpiperazine-l-carboxylate:

[00290] To a stirred solution of tert-butyl (3R)-3-methyl-4-[6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (2.20 g, 6.58 mmol, 1.00 equiv) in DMF (30 mL) was added NBS (1.29 g, 7.24 mmol, 1.10 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 3h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched by the addition of sat.NaHCO3(aq) (30 mL) at 0°C. The resulting mixture was poured into water (100 mL), extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3x150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to afford tert-butyl (3R)-4-[2-bromo-6-(methylcarbamoyl)pyridin-3-yl]-3-methylpiperazine-1-carboxylate (1.77 g, 65%) as a light yellow oil. LCMS: (ES+H, m / z): [M+H]+ = 413.0 / 415.0. 'HNMR (300 MHz, DMSO-d6) 5 8.47 (d, 1H), 7.97 (d, 1H), 7.75 (d, 1H), 3.66 - 3.48 (m, 4H), 3.27-3.18(m, 2H), 2.80 (d, 3H), 2.73 - 2.60 (m, 1H), 1.43 (s, 9H), 0.84 (d, 3H). Step 2: Preparation of tert-butyl (3R)-4-[2-cyano-6-(methylcarbamoyl)pyridin-3-yl]-3-methylpiperazine-l-carboxylate:

[00291] A mixture of tert-butyl (3R)-4-[2-bromo-6-(methylcarbamoyl)pyridin-3-yl]-3-methylpiperazine-l-carboxylate (500 mg, 1.21 mmol, 1.00 equiv), Zn(CN)2 (156 mg, 1.33 mmol, 1.10 equiv) and Pd(PPh3)4 (140 mg, 0.12 mmol, 0.10 equiv) in DMF (8 mL) was stirred overnight at 120°C under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was poured into water (100 mL), extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford tert-butyl (3R)-4-[2-cyano-6-(methylcarbamoyl)pyridin-3-yl]-3-methylpiperazine-l-carboxylate (428 mg, 98%) as a yellow solid. LC-MS: (ES-H, m / z): [M-H]’ = 358.1. 1HNMR(400 MHz, DMSO-d6) 5 8.60 (d,lH), 8.12 (d,lH), 7.81 (d,lH), 3.41 - 3.33 (m, 4H), 3.21 (d,2H), 2.80 (d,3H),2.52-2.51(m,lH), 1.43 (s, 9H), 1.02 (d,3H). Step 3: Preparation of 6-cyano-N-methyl-5-[(2R)-2-methylpiperazin-l-yl]pyridine-2-carboxamide, HC1 salt:

[00292] A solution of tert-butyl (3R)-4-[2-cyano-6-(methylcarbamoyl)pyridin-3-yl]-3-methylpiperazine-l-carboxylate (135 mg, 0.38 mmol, 1.00 equiv) and HCl(gas)in 1,4-dioxane (5 mL, 4M) in DCM (5 mL) was stirred for 3h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to afford 6-cyano-N-methyl-5-[(2R)-2-methylpiperazin-l-yl]pyridine-2-carboxamide, HC1 salt (310 mg, crude) as a light yellow solid. The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+ = 260.2 Step 4: Preparation of 6-cyano-5-[(2R)-4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]-2-methylpiperazin-l-yl]-N-methylpyridine-2-carboxamide:

[00293] To a stirred mixture of 6-cyano-N-methyl-5-[(2R)-2-methylpiperazin-l-yl]pyridine-2-carboxamide, HC1 salt (250 mg, crude) and DIEA (498 mg, 3.86 mmol, 5.00 equiv) in MeCN (8 mL) were added 7-(chloromethyl)-3-ethyl-lH-l,5-naphthyridin-2-one (172 mg, 0.77 mmol, 1.00 equiv) and KI (26 mg, 0.15 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred for 4h at 80°C under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, the pure fraction was concentrated under reduced pressure to afford 6-cyano-5 -[(2R)-4- [(7-ethyl-6-oxo-5H-1,5 -naphthyridin-3 -yl)methyl] -2-methylpiperazin-1 -yl] -N-methylpyridine-2-carboxamide (135.4 mg, 39%, ee=97.6%) as a light yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 446.1. 1HNMR(400 MHz, DMSO-d6) 5 11.89 (s, 1H), 8.58 (d, 1H), 8.42 (d, 1H), 8.12 (d, 1H), 7.81 (d, 1H), 7.75 (s, 1H), 7.65 (d, 1H), 4.02 (m, 1H), 3.74 - 3.58 (m, 2H), 3.47-3.39 (m, lH),3.28-3.20(m, 1H) 2.79 (m, 4H), 2.58 - 2.53 (m, 4H), 2.42 (t, 1H), 1.19 (t, 3H), 1.13 (d, 3H). Example 5 1                                                    3                                            4 over three steps Step 1: Preparation of tert-butyl 4-(5-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-l-carboxylate:

[00294] A mixture of methyl 5-bromo-3-fluoropyridine-2-carboxylate (1.00 g, 4.27 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (0.84 g, 4.48 mmol, 1.05 equiv), RuPhos Palladacycle Gen.3 (0.36 g, 0.43 mmol, 0.10 equiv) and CS2CO3 (2.78 g, 8.55 mmol, 2.00 equiv) in 1,4-dioxane (16 mL) was stirred overnight at 110°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-[5-fluoro-6-(methoxycarbonyl)pyridin-3-yl]piperazine-l-carboxylate (1.00 g, 68.96%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=339.9. 1HNMR(300 MHz, DMSO-d6) 5 8.24 (s, 1H), 7.23 (dd, 1H), 3.81 (s, 3H), 3.56 -3.36 (m, 8H), 1.43 (s, 9H). Step 2: Preparation of tert-butyl 4-(5-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazine-l-carboxylate:

[00295] To a stirred solution of ethyl 4-[5-fluoro-6-(methoxycarbonyl)pyridin-3-yl]piperazine-l-carboxylate (1.20 g, 3.86 mmol, 1.00 equiv) in methanol (8 mL) was added CH3NH2 (8 mL, 25%-30% in water) at room temperature. The resulting mixture was stirred for Ih at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with sat. NH4CI (aq., 100 mL) at 0°C. The resulting mixture was extracted with CH2CI2 (3 xlOO mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford crude product (1.22g) as a white solid. The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+ =338.9. ‘H NMR (400 MHz, DMSO-d6) 5 8.29 (q, IH), 8.14 (d, IH), 7.23 (d, IH), 3.55 - 3.34 (m, 8H), 2.75 (d, 3H), 1.42 (s, 9H). Step 3: Preparation of 3-fluoro-N-methyl-5-(piperazin-l-yl)picolinamide:

[00296] To a stirred solution of 3-fluoro-N-methyl-5-(piperazin-l-yl)pyridine-2-carboxamide (1.22 g, 5.12 mmol, 1.00 equiv) in 1,4-dioxane (5 mL) was added HC1 (gas) in 1,4-dioxane (10 mL, 4M) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for Ih at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexane:ether=l: 1 (10 mL x 3) to afford crude product (1.22 g, HC1 salt) as a white solid. The crude product was used in the next step directly. LC-MS: (ES+H, m / z): [M+H]+ =238.9. Step 4: Preparation of 5-(4-((7-ethyl-6-oxo-5,6-dihydro-l,5-naphthyridin-3-yl)methyl)piperazin-l-yl)-3-fluoro-N-methylpicolinamide:

[00297] To a stirred solution of 3-fluoro-N-methyl-5-(piperazin-l-yl)pyridine-2-carboxamide (80 mg, assumed 100% yield, 0.34 mmol, 1.50 equiv) and 7-(chloromethyl)-3-ethyl-lH-l,5-naphthyridin-2-one (50 mg, 0.22 mmol, 1.00 equiv) in ACN (5 mL) was added KI (7 mg, 0.04 mmol, 0.20 equiv) and DIEA (145 mg, 1.12 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred for 3h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to r.t. The resulting mixture was concentrated under reduced pressure. The residue was purified by PREPHPLC. The pure fractions were concentrated and lyophilized to afford 5-(4-((7-ethyl-6-oxo-5,6-dihydro-l,5-naphthyridin-3-yl)rnethyl)piperazin-l-yl)-3-fluoro-N-methylpicolinamide (34 mg, 34.24%, over three steps) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =424.90. 1HNMR(400 MHz, DMSO-d6) 5 11.87 (s, 1H), 8.40 (s, 1H), 8.27 (q, 1H), 8.13 (s, 1H), 7.75 (s, 1H), 7.62 (s, 1H), 7.22 (dd, 1H), 3.65 (s, 2H), 3.45 - 3.34 (m, 4H), 2.74 (d, 3H), 2.58 - 2.51 (m, 6H), 1.18 (t, 3H). 19F NMR (377 MHz, DMSO) 5 -120.40. Example 6 Step 1: Preparation of tert-butyl 4-(2-bromo-6-(methylcarbamoyl)pyridin-3-yl)piperazine-l-carboxylate:

[00298] To a stirred solution of tert-butyl 4-[6-(methylcarbamoyl)pyridin-3-yl]piperazine-l-carboxylate (2.00 g, 6.24 mmol, 1.00 equiv) in DMF (10 ml) was added NBS (1.22 g, 6.87 mmol, 1.10 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of sat. NaHCO3 (aq.) (5 mL) at 0 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to afford tert-butyl 4-(2-bromo-6-(methylcarbamoyl)pyridin-3-yl)piperazine-l-carboxylate (2.40 g, 96.29%) as a colorless oil. LC-MS: (ES+H, m / z): [M+H]+ =399.1 / 401.1. 1 HNMR (400 MHz, DMSO-d6) 5 8.44 (q, 1H), 7.96 (d, 1H), 7.65 (d, 1H), 3.60-3.41 (m, 4H), 3.10 - 2.98 (m, 4H), 2.80 (d, 3H), 1.43 (s, 9H). Step 2: Preparation of tert-butyl 4-(2-cyclopropyl-6-(methylcarbamoyl)pyridin-3-yl)piperazine-l-carboxylate:

[00299] A mixture of tert-butyl 4-[2-bromo-6-(methylcarbamoyl)pyridin-3-yl]piperazine-l-carboxylate (1.20 g, 3.00 mmol, 1.00 equiv), Pd(dppf)C12 (0.22 g, 0.30 mmol, 0.10 equiv), CS2CO3 (1.96 g, 6.01 mmol, 2.00 equiv) and cyclopropylboronic acid (0.26 g, 3.00 mmol, 1.00 equiv) in Toluene / H2O (10 mL / 1 mL) was stirred for 1,5h at 100°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to r.t. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to afford tert-butyl 4-(2-cyclopropyl-6-(methylcarbamoyl)pyridin-3-yl)piperazine-l-carboxylate (900 mg, 83.08%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =361.1. 'HNMR (300 MHz, DMSO-d6) 5 8.28 (q, 1H), 7.71 (d, 1H), 7.44 (d, 1H), 3.64 - 3.43 (m, 4H), 3.06 - 2.89 (m, 4H), 2.80 (d, 3H), 2.45 - 2.32 (m, 1H), 1.43 (s, 9H), 1.22-1.13 (m, 2H), 1.07-0.88 (m, 2H). Step 3: Preparation of 6-cyclopropyl-N-methyl-5-(piperazin-l-yl)picolinamide, HC1 salt:

[00300] To a stirred solution of tert-butyl 4-[2-cyclopropyl-6-(methylcarbamoyl)pyridin-3-yl]piperazine-l-carboxylate (900 mg, 2.50 mmol, 1.00 equiv) in 1,4-dioxane (3 ml) were added HCl(gas)in 1,4-dioxane (10.00 mL, 4 M) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by trituration with hexane:ether=l: 1 (10 mL x 3). to afford 6-cyclopropyl-N-methyl-5-(piperazin-l-yl)picolinamide, HC1 salt (900 mg, crude) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =261.2. Step 4: Preparation of 6-cyclopropyl-5-(4-((7-ethyl-6-oxo-5,6-dihydro-l,5-naphthyridin-3-yl)methyl)piperazin-l-yl)-N-methylpicolinamide:

[00301] To a stirred mixture of 7-(chloromethyl)-3-ethyl-lH-l,5-naphthyridin-2-one (100 mg, 0.45 mmol, 1.00 equiv) and 6-cyclopropyl-N-methyl-5-(piperazin-l-yl)pyridine-2-carboxamide, HC1 salt (200 mg, 0.67 mmol, 1.50 equiv) in MeCN (10 mL) were added KI (15 mg, 0.09 mmol, 0.20 equiv) and DIEA (290 mg, 2.25 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to r.t. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC. The pure fractions were concentrated and lyophilized to afford 6-cyclopropyl-5-(4-((7-ethyl-6-oxo-5,6-dihydro-l,5-naphthyridin-3-yl)methyl)piperazin-l-yl)-N-methylpicolinamide (31 mg, 15.51%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =447.0. 1HNMR(400 MHz, DMSO-d6) 5 11.87 (s, 1H), 8.41 (d, 1H), 8.32 - 8.21 (m, 1H), 7.75 (s, 1H), 7.70 (d, 1H), 7.62 (s, 1H), 7.43 (d, 1H), 3.68 (s, 2H), 3.15 - 2.90 (m, 4H), 2.78 (d, 3H), 2.69-2.54 (m, 6H), 2.36 - 2.29 (m, 1H), 1.22-1.10 (m, 5H), 1.01-0.91 (m, 2H). Example 7 Step 1: Preparation of tert-butyl 4-[3-fluoro-4-(methoxycarbonyl)phenyl]piperazine-l-carboxylate:

[00302] To a stirred mixture of methyl 4-bromo-2-fluorobenzoate (1.00 g, 4.29 mmol, 1.00 equiv) and tert butyl piperazine-1-carboxylate (0.84 g, 4.51 mmol, 1.05 equiv) in dioxane (100 mL) were added CS2CO3 (2.80 g, 8.58 mmol, 2.00 equiv) and RuPhos Palladacycle Gen.3 (0.18 g, 0.22 mmol, 0.05 equiv) at room temperature. The resulting mixture was stirred for 6 h at 120 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was fdtered, the filter cake was washed with EtOAc (3x100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-[3-fluoro-4-(methoxycarbonyl)phenyl]piperazine-l-carboxylate (1.30 g, 89%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+ =339.2. Tf NMR (300 MHz, DMSO-d6) 5 7.72 (t, 1H), 6.84 - 6.69 (m, 2H), 3.77 (s, 3H), 3.48 - 3.33 (m, 8H), 1.43 (s, 9H). Step 2: Preparation of tert-butyl 4-[3-fluoro-4-(methylcarbamoyl)phenyl]piperazine-l-carboxylate:

[00303] A mixture of tert-butyl 4-[3-fluoro-4-(methoxycarbonyl)phenyl]piperazine-l-carboxylate (1.3 g, 3.84 mmol, 1.00 equiv) in MeOH (5 mL) was added Methylamine (3.5 mL, 25-30%wt in water) dropwise. And the mixture was stirred overnight at 50 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL).The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed combi-flash chromatography. The resulting mixture was concentrated under reduced pressure to afford tert-butyl 4-[3-fluoro-4-(methylcarbamoyl)phenyl]piperazine-l-carboxylate (1.00 g, 77%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =338.2. Tf NMR (300 MHz, DMSO-d6) 5 7.78 (d, 1H), 7.58 (t, 1H), 6.85 -6.68 (m, 2H), 3.45-3.40 (m, 4H), 3.27 (dd, 4H), 2.76 (d, 3H), 1.43 (s, 9H). Step 3: Preparation of 2-fluoro-N-methyl-4-(piperazin-l-yl)benzamide, HC1 salt:

[00304] To a stirred mixture of tert-butyl 4-[3-fluoro-4-(methylcarbamoyl)phenyl]piperazine-l-carboxylate (500 mg, 1.48 mmol, 1.00 equiv) in DCM (4 mL) was added HCl(gas)in 1,4-dioxane (2 mL, 4M) dropwise at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexaneethyl ether:ethyl ether=l: 1 (4 mL). The resulting mixture was concentrated under reduced pressure to afford 2-fluoro-N-methyl-4-(piperazin-l-yl)benzamide, HC1 salt (500 mg, crude) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =237.9. 'HNMR (400 MHz, DMSO-d6) 5 9.46 (s, 2H), 7.92 - 7.79 (m, 1H), 7.60 (t, 1H), 6.91 - 6.72 (m, 2H), 3.54 (m, 4H), 3.17 (m, 4H), 2.75 (d, 3H). Step 4: Preparation of 4-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl}-2-fluoro-N-methylbenzamide:

[00305] To a stirred mixture of 7-(chloromethyl)-3-ethyl-lH-l,5-naphthyridin-2-one, HC1 salt (100 mg, 0.45 mmol, 1.00 equiv) and 2-fluoro-N-methyl-4-(piperazin-l-yl)benzamide hydrochloride (123 mg, 0.45 mmol, 1.00 equiv) in MeCN (5 mL) were added KI (15 mg, 0.09 mmol, 0.20 equiv) and DIEA (290 mg, 2.24 mmol, 5.00 equiv). The resulting mixture was stirred for 3 h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC, and the pure fractions were concentrated and lyophilized to afford 4-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl}-2-fluoro-N-methylbenzamide (14 mg, 7%) as an off-white solid. LC-MS: (ES+H, m / z): [M+H]+ =423.90. ’H NMR (400 MHz, DMSO-d6) 5 11.86 (s, 1H), 8.40 (d, 1H), 7.76 (d, 2H), 7.66 - 7.48 (m, 2H), 6.86 - 6.66 (m, 2H), 3.64 (s, 2H), 3.30 (d, 4H), 3.28 (d, 4H), 2.74 (d, 3H), 2.56 - 2.53 (m, 2H), 1.18 (t, 3H). 19F NMR (377 MHz, DMSO) 5 -111.58. Example 8 Step 1: Preparation of l'-(tert-butyl) 6-methyl 3',6'-dihydro-[3,4'-bipyridine]-l',6(2'H)-dicarboxylate:

[00306] A solution of tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (859 mg, 2.78 mmol, 1.20 equiv), methyl 5-bromopyridine-2-carboxylate (500 mg, 2.31 mmol, 1.00 equiv), K2CO3 (640 mg, 4.63 mmol, 2.00 equiv) and Pd(dppf)C12 (339 mg, 0.46 mmol, 0.2 equiv) in 1,4-dioxane (10 mL) and H2O (2 mL) was stirred overnight at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to RT. The resulting mixture was diluted with H2O (50 mL). The resulting mixture was extracted with EA (3x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford l'-(tert-butyl) 6-methyl 3',6'-dihydro-[3,4'-bipyridine]-r,6(2'H)-dicarboxylate (260 mg, 29.41%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+ =319.1. XH NMR (300 MHz, DMSO-d6) 5 8.82 (dd, 1H), 8.02 (t, 2H), 6.46 (s, 1H), 4.06 (d, 2H), 3.88 (s, 3H), 3.57 (t, 2H), 2.54 (s, 2H), 1.44 (s, 9H). Step 2: Preparation of tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-l'(2'H)-carboxylate:

[00307] To a stirred solution of 1'-(tert-butyl) 6-methyl 3',6'-dihydro-[3,4'-bipyridine]-l',6(2'H)-dicarboxylate (210 mg, 0.66 mmol, 1.00 equiv) in methanol (3 mL) was added CH3NH2 (3 mL, 25-30%wt in water) at room temperature. The resulting mixture was stirred for Ih at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of sat. NH4CI (aq.) (50 mL) at room temperature. The aqueous layer was extracted with EtOAc (3x50 mL). The combined organic layers were concentrated under reduced pressure to afford tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-l'(2'H)-carboxylate (190 mg, 90.76%) as a purple solid. LC-MS: (ES+H, m / z): [M+H]+ =318.2. ’H NMR (400 MHz, DMSO-d6) 5 8.76 - 8.68 (m, 2H), 8.08 - 7.86 (m, 2H), 6.34 (d, IH), 4.05 (d, 2H), 3.56 (t, 2H), 2.82 (d, 4H), 2.54 (d, IH), 1.43 (s, 9H). Step 3: Preparation of N-methyl-l',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide, TFA salt:

[00308] To a stirred solution of tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-2'H-[3,4'-bipyridine]-l'-carboxylate (170 mg, 0.54 mmol, 1 equiv) in DCM (5 mL) was added TFA (1 mL) dropwise at room temperature under air atmosphere. The resulting mixture was stirred for Ih at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+ =218.1 Step 4: Preparation of l'-((7-ethyl-6-oxo-5,6-dihydro-l,5-naphthyridin-3-yl)methyl)-N-methyl-l',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide:

[00309] To a stirred mixture of N-methyl-T,2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (101 mg, 0.50 mmol, 1.00 equiv) and 7-(chloromethyl)-3-ethyl-l,5-naphthyridin-2(lH)-one (111 mg, 0.50 mmol, 1.00 equiv) in MeCN (5 mL) were added KI (17 mg, 0.10 mmol, 0.20 equiv) and DIEA (323 mg, 2.50 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred for Ih at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC. The pure fractions were concentrated and lyophilized to afford l'-((7-ethyl-6-oxo-5,6-dihydro-l,5-naphthyridin-3-yl)methyl)-N-methyl-l',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (39.6 mg, 18.49%, over two steps) as a light yellow solid. LCMS: (ES+H, m / z): [M+H]+ =404.2. 1HNMR(400 MHz, DMSO-d6) 5 11.85 (s, IH), 8.70 (t, 2H), 8.42 (s, IH), 8.05 - 7.93 (m, 2H), 7.76 (s, IH), 7.65 (s, IH), 6.42 (s, IH), 3.73 (s, 2H), 3.16 (s, 2H), 2.81 (d, 3H), 2.71 (s, 2H), 2.60 - 2.52 (m, 4H), 1.19 (t, 3H). The following examples were made using similar procedures shown for example 8. Ex NMR LCMS (ESI) m / z 64 ‘H NMR (300 MHz, DMSO-d6) 5 11.88 (s, IH), 8.72 (d, 2H), 8.40 (d, IH), 7.98 (s, 2H), 7.63 (s, IH), 7.43 (s, IH), 6.43 (s, IH), 3.72 (s, 2H), 3.16 (d, 2H), 2.82 (d, 3H), 2.70 (d, 2H), 2.56 (m, 2H), 2.16 (dt, IH), 1.03 - 0.93 (m, 2H), 0.85-0.82 (m, 2H). M+H]+=416.25 Example 9 Step 1: Preparation of 7-(chloromethyl)-3-ethyl-lH-quinolin-2-one:

[00310] To a stirred mixture of 3-ethyl-7-(hydroxymethyl)-lH-quinolin-2-one (1.00 g, 4.92 mmol, 1.00 equiv) and DMF (18 mg, 0.25 mmol, 0.05 equiv) in DCM (20 mL) was added SOCh (1.76 g, 14.76 mmol, 3.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to afford 7-(chloromethyl)-3-ethyl-lH-quinolin-2-one (1.00 g, 91.68%) as an off-white solid. MS: (ES+H, m / z): [M+H]+ =222.1 Step 2: Preparation of 6-{4-[(3-ethyl-2-oxo-lH-quinolin-7-yl)methyl]piperazin-l-yl}pyridine-3-carbonitrile :

[00311] To a stirred mixture of 7-(chloromethyl)-3-ethyl-lH-quinolin-2-one (100 mg, 0.45 mmol, 1.20 equiv), 6-(piperazin-l-yl)pyridine-3-carbonitrile (71 mg, 0.38 mmol, 1.00 equiv) and KI (12 mg, 0.08 mmol, 0.20 equiv) in MeCN (5 mL) was added DIEA (243 mg, 1.88 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (100 mg) was purified by Prep-HPLC to afford 6-{4-[(3-ethyl-2-oxo-lH-quinolin-7-yl)methyl]piperazin-l-yl}pyridine-3-carbonitrile (35.2 mg, 25.07%) as an off-white solid. MS: (ES+H, m / z): [M+H]+ =374.2. 1H NMR (300 MHz, DMSO-d6) 5 11.68 (s, 1H), 8.48 (d, 1H), 7.84 (dd, 1H), 7.70 (s, 1H), 7.57 (d, 1H), 7.27 (s, 1H), 7.13 (d, 1H), 6.92 (d, 1H), 3.67 (s, 4H), 3.57 (s, 2H), 2.50-2.47 (m, 6H), 1.16 (t, 3H). Example 10 Step 1: Preparation of N-(3-bromophenyl)-2-oxocyclopentane-l-carboxamide:

[00312] A solution of 4-(cyclopent-l-en-l-yl) morpholine (3.60 g, 23.49 mmol, 1.00 equiv.) and 1-bromo-3-isocyanatobenzene (5.58 g, 28.19 mmol, 1.20 equiv.) in CHC13 (100 mL) was stirred for 4h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, the pure fraction was concentrated under vacuum to afford N-(3-bromophenyl)-2-oxocyclopentane-1 -carboxamide (3.9 g, 58.8%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =281.9 / 283.9. 1HNMR(300 MHz, Chloroform-d) 5 8.83 (s, 1H), 7.84 (t, 1H), 7.45-7.41 (m, 1H), 7.29 - 7.15 (m, 2H), 3.20 - 3.11 (m, 1H), 2.51 -2.33 (m, 4H), 2.17-2.05 (m, 1H), 1.96-1.83 (m, 1H). Step 2: Preparation of 7-bromo-lH,2H,3H,5H-cyclopenta[c]quinolin-4-one:

[00313] To a stirred solution of H2SO4 (10 mL) was added N-(3-bromophenyl)-2-oxocyclopentane-l-carboxamide (3,3 g, 11.69 mmol, 1.00 equiv.) slowly at 0°C.The resulting mixture was stirred for 4h at room temperature. The reaction was monitored by LCMS. The mixture was basified with aq.Na2CO3 (200 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4. After fdtration, the fdtrate was concentrated under reduced pressure to afford 7-bromo-lH,2H,3H,5H-cyclopenta[c]quinolin-4-one (2.10 g, 67.9%) as a white solid. The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+ =264.0 / 266.0. 'HNMR (300 MHz, DMSO-d6) 8 11.66 (s, 1H), 7.52-7.43 (m, 2H), 7.33 (dd, 1H), 3.06 (t, 2H), 2.74 (t, 2H), 2.14-1.99 (m, 2H). Step 3: Preparation of ethyl 4-oxo-lH,2H,3H,5H-cyclopenta[c]quinoline-7-carboxylate:

[00314] To a solution of 7-bromo-lH,2H,3H,5H-cyclopenta[c]quinolin-4-one (1.50 g, 5.67 mmol, 1.00 equiv.) and EhN (1.15 g, 11.35 mmol, 2.00 equiv.) in EtOH (20 mL) was added Pd(PPh3)2C12 (797 mg, 1.13 mmol, 0.20 equiv.) in pressure tank. The mixture was purged with nitrogen for 3 min and then was pressurized to 40 atm with carbon monoxide at 120°C for overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The residue was purified by silica gel column chromatography, the pure fraction was concentrated under vacuum to afford ethyl 4-oxo-lH,2H,3H,5H-cyclopcnta|c|quinoline-7-carboxylate (750 mg, 51.33%) as a light yellow solid. LC-MS: (ES+H, m / z): [M+H]+=258.2 Step 4: Preparation of 7-(hydroxymethyl)-lH,2H,3H,5H-cyclopenta[c]quinolin-4-one:

[00315] To a stirred solution of ethyl 4-oxo-lH,2H,3H,5H-cyclopenta[c]quinoline-7-carboxylate (650 mg, 2.52 mmol, 1.00 equiv.) in THF (3 mL) at 0°C under nitrogen atmosphere. To the above mixture was added LiAlH4 (2.02 mL, 5.05 mmol, 2.00 equiv., 2.5M in THF) dropwise over 3min at 0°C. The resulting mixture was stirred for additional 2h at room temperature. The reaction was monitored by LCMS. The reaction was quenched by the addition of H2O (0.3 mL) at 0°C. Then added NaOH (15%wt, 1.4 mL) stirred for 10 min at room temperature. The reaction was added addition of H2O (0.3 mL) and stirred for additional 10 min. The resulting mixture was filtered, the filter cake was washed with THF (3x5 mL), dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography, the pure fraction was concentrated under vacuum to afford 7-(hydroxymethyl)-lH,2H,3H,5H-cyclopenta[c]quinolin-4-one (300 mg, 55.1%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =216.2. 1HNMR(400 MHz, DMSO-d6) 8 11.56 (s, 1H), 7.47 (d, 1H), 7.33 (s, 1H), 7.12 - 7.08 (m, 1H), 5.34 (t, 1H), 4.57 (d, 2H), 3.07 (t, 2H), 2.75 (t, 2H), 2.13 - 2.06 (m, 2H). Step 5: Preparation of 7-(chloromethyl)-lH,2H,3H,5H-cyclopenta[c]quinolin-4-one:

[00316] To a stirred solution of 7-(hydroxymethyl)-lH,2H,3H,5H-cyclopenta[c]quinolin-4-one (350 mg, 1.62 mmol, 1.00 equiv.) and DMF (12 mg, 0.16 mmol, 0.10 equiv.) in DCM (2 mL) was added SOCI2 (967 mg, 8.13 mmol, 5.00 equiv.) dropwise at 0°C.The resulting mixture was stirred for 2h at room temperature. The reaction was monitored by LCMS. The resulting mixture was washed with DCM (3 x 30 mL). The resulting mixture was concentrated under vacuum to afford 7-(chloromethyl)-3-ethyl-4-fluoro-lH-quinolin-2-one (390 mg, crude) as an orange solid. The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m / z)'. [M+H]+=234.0 Step 6: Preparation of N-methyl-5-[4-({4-oxo-lH,2H,3H,5H-cyclopenta[c]quinolin-7-yl}methyl)piperazin-l-yl]pyridine-2-carboxamide:

[00317] To a stirred solution of 7-(chloromethyl)-lH,2H,3H,5H-cyclopenta[c]quinolin-4-one (150 mg, 0.64 mmol, 1.00 equiv.) and N-methyl-5-(piperazin-l-yl)pyridine-2-carboxamide (148 mg, 0.67 mmol, 1.05 equiv.) in MeCN (3 mL) were added DIEA (415 mg, 3.21 mmol, 5.00 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, the pure fraction was concentrated under vacuum to afford N-methyl-5-[4-({4-oxo-lH,2H,3H,5H-cyclopenta[c]quinolin-7-yl}methyl)piperazin-l-yl]pyridine-2-carboxamide (34.1 mg, 12.1%) as a light brown solid. LC-MS: (ES+H, m / z): [M+H]+ =418.2. 1HNMR(300 MHz, DMSO-d6) 5 11.55 (s, 1H), 8.41 (d, 1H), 8.27 (d, 1H), 7.83 (d, 1H), 7.50 (d, 1H), 7.42 - 7.30 (m, 2H), 7.17 (d, 1H), 3.59 (s, 2H), 3.34-3.32 (m, 4H) 3.08 (t, 2H), 2.78-2.74 (m, 5H), 2.55-2.54 (d, 4H), 2.15-2.05 (m, 2H). Example 11 Step 1: Preparation of methyl 3-(furan-3-amido)-4-iodobenzoate:

[00318] A mixture of methyl 3-amino-4-iodobenzoate (10.00 g, 36.09 mmol, 1.00 equiv), 3-furoic acid (8.09 g, 72.18 mmol, 2.00 equiv), T3P (114.84 g, 180.46 mmol, 5.00 equiv, 50%wt in EA) and DIEA (23.32 g, 180.46 mmol, 5.00 equiv) in DCM (100 mL) was stirred overnight at 60 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (150 mL), and was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4. After fdtration, the fdtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford methyl 3-(furan-3-amido)-4-iodobenzoate (6.80 g, 50.76%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =372.0. Step 2: Preparation of methyl 3-[N-(tert-butoxycarbonyl)furan-3-amido]-4-iodobenzoate:

[00319] A solution of methyl 3-(furan-3-amido)-4-iodobenzoate (6.00 g, 16.167 mmol, 1.00 equiv), (Boc)2O (7.06 g, 32.34 mmol, 2.00 equiv) and DMAP (1.98 g, 16.17 mmol, 1.00 equiv) in DCE (100 mL) was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (250 mL), and was washed with water (2 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford methyl 3-[N-(tert-butoxycarbonyl)furan-3-amido]-4-iodobenzoate (5.00 g, 65.63%) as awhite solid. 1HNMR(300 MHz, DMSO-d6) 5 8.31 (dd, 1H), 8.13 (d, 1H), 7.90 (d, 1H), 7.79 (t, 1H), 7.69 (dd, 1H), 6.79 (dd, 1H), 3.87 (s, 3H), 1.34 (s, 9H). Step 3: Preparation of methyl 4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate:

[00320] To a mixture of methyl 3-[N-(tert-butoxycarbonyl)furan-3-amido]-4-iodobenzoate (400 mg, 0.85 mmol, 1.00 equiv) and PCy, (48 mg, 0.17 mmol, 0.20 equiv) in DMF (12 mL) were added Pd(OAc)2 (38 mg, 0.17 mmol, 0.20 equiv) and K2CO3 (235 mg, 1.70 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. The final reaction mixture was irradiated with microwave radiation for 2 h at 100 °C. The mixture was allowed to cool down to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (50 mL). The resulting mixture was washed with water (2 x 25 mL). The combined organic layers were washed with brine (2x25 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford methyl 4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate (120 mg, 58.13%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+ =244.0. Step 4: Preparation of 7-(hydroxymethyl)-5H-furo[3,2-c]quinolin-4-one:

[00321] To a stirred mixture of methyl 4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate (300 mg, 1.23 mmol, 1.00 equiv) in THF (2 mL) was added LiAlH4 (0.99 mL, 2.47 mmol, 2.00 equiv, 2.5M in THF) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for Ih at 0°C under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of IM aq HC1 (1.2 mL) at 0°C. The residue was purified by silica gel column chromatography to afford 7-(hydroxymethyl)-5H-furo[3,2-c]quinolin-4-one (220 mg, 82.88%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=216.1. Step 5: Preparation of 7-(chloromethyl)-5H-furo[3,2-c]quinolin-4-one:

[00322] To a stirred mixture of 7-(hydroxymethyl)-5H-furo[3,2-c]quinolin-4-one (300 mg, 1.39 mmol, 1.00 equiv) and DMF (10 mg, 0.14 mmol, 0.10 equiv) in DCM (5 mL) was added SOCI2 (995 mg, 8.36 mmol, 6.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at 0°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 7-(chloromethyl)-5H-furo[3,2-c]quinolin-4-one (240 mg, 73.69%) as a white solid. LC-MS: (ES+H, m / zy [M+H]+=234.0. Step 6: Preparation of N-methyl-5-[4-({4-oxo-5H-furo[3,2-c]quinolin-7-yl}methyl)piperazin-l-yl]pyridine-2-carboxamide:

[00323] A mixture of 7-(chloromethyl)-5H-furo[3,2-c]quinolin-4-one (100 mg, 0.43 mmol, 1.00 equiv), N-methyl-5-(piperazin-l-yl)picolinamide, HC1 salt (110 mg, 0.43 mmol, 1.00 equiv), KI (14 mg, 0.09 mmol, 0.20 equiv) and DIEA (276 mg, 2.14 mmol, 5.00 equiv) in MeCN (10 mL) was stirred for 2 h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford N-methyl-5-[4-({4-oxo-5H-furo[3,2-c]quinolin-7-yl}methyl)piperazin-l-yl]pyridine-2-carboxamide (95 mg, 51.63%) as a white solid. LC-MS: (ES+H, m / zy. [M+H]+=418.20. 1HNMR(400 MHz, DMSO-d6) 5 11.70 (s, 1H), 8.40 (q, 1H), 8.27 (d, 1H), 8.08 (d, 1H), 7.89 (d, 1H), 7.83 (d, 1H), 7.46 (s, 1H), 7.39 (dd, 1H), 7.28 (dd, 1H), 7.06 (d, 1H), 3.63 (s, 2H), 3.39 - 3.34 (m, 4H), 2.78 (d, 3H), 2.56 (m, 4H). Example 12 Example 12 Step 1: Preparation of 5-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl}pyridine-2-carboxylic acid:

[00324] To a stirred solution of methyl 5-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl}pyridine-2-carboxylate (120 mg, 0.29 mmol, 1.00 equiv) in EtOH / THF (1:1, 5 mL) was added aqueous NaOH (3.0 mL, IN) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for additional Ih at room temperature. The reaction was monitored by LCMS. And then 1(N) aqueous HC1 (3.0 mL) was added. The reaction was concentrated under reduced pressure to afford 5-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl}pyridine-2-carboxylic acid (150 mg) as a white solid, (used without further purification). LC-MS: (ES+H, m / zy [M+H]+=394.2. Step 2: Preparation of N-cyclopropyl-5-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl}pyridine-2-carboxamide:

[00325] To a stirred solution of 5-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl}pyridine-2-carboxylic acid (120 mg, 0.30 mmol, 1.00 equiv) and DIEA (158 mg, 1.22 mmol, 4.00 equiv) in DMF (4 mL) was added HATU (174 mg, 0.46 mmol, 1.50 equiv) at room temperature under nitrogen atmosphere. To the above mixture was added aminocyclopropane (35 mg, 0.61 mmol, 2.00 equiv) and stirred at room temperature overnight. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1x5 mL), dried over anhydrous Na2SO4. After filtration, the fdtrate was concentrated under reduced pressure. The residue was purified by reversed combi-flash chromatography, the pure fractions were concentrated and lyophilized to afford N-cyclopropyl-5-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl}pyridine-2-carboxamide (23.1 mg, 17%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =433.2. 'HNMR (300 MHz, DMSO-d6) 5 11.85 (s, 1H), 8.41 (s, 1H), 8.35 (s, 1H), 8.24 (s, 1H), 7.83 (d, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.40 (d, 1H), 3.65 (s, 2H), 3.30 - 3.14 (m, 6H), 2.85 (s, 1H), 2.65 - 2.53 (m, 4H), 1.18 (t, 3H), 0.69 - 0.57 (m, 4H). Example 13 Step 1: Preparation of methyl 5-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl}pyridine-2-carboxylate:

[00326] To a stirred mixture of methyl 5-(piperazin-l-yl)pyridine-2-carboxylate (280 mg, 1.26 mmol, 1.00 equiv) and DIEA (818 mg, 6.32 mmol, 5.00 equiv) in MeCN (6 mL) were added 7-(chloromethyl)-3-ethyl-lH-l,5-naphthyridin-2-one (282 mg, 1.26 mmol, 1.00 equiv) and KI (42 mg, 0.25 mmol, 0.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to afford methyl 5-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl}pyridine-2-carboxylate (300 mg, 58%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =408.1. Step 2: Preparation of 5-(4-((7-ethyl-6-oxo-5,6-dihydro-l,5-naphthyridin-3-yl)methyl)piperazin-l-yl)picolinic acid:

[00327] To a stirred solution of methyl 5-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl}pyridine-2-carboxylate (200 mg, 0.49 mmol, 1.00 equiv) in EtOH / THF (5 mL / 5 mL) was added 5.0 mL 1(N) aqueous NaOH at room temperature under nitrogen atmosphere. The resulting mixture was stirred for additional 2 hours at room temperature. The reaction solution was neutralized with lmol / 1 hydrochloric acid and the organic solvent was then distilled off under reduced pressure. After filtering off the obtained residue, it was washed with water and concentrated under reduced pressure to afford the title compound (140 mg, 73%) as a white solid. LC-MS: (ES+H, m / zy [M+H]+ =394.2. Step 3: Preparation of N-(2,2-difluoroethyl)-5-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl) methyl] piperazin-l-yl} pyridine-2-carboxamide:

[00328] To a stirred solution of 5-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl) methyl]piperazin-l-yl}pyridine-2-carboxylic acid (220 mg, 0.56 mmol, 1.00 equiv) and DIEA (361 mg, 2.80 mmol, 5.00 equiv) in DMF (5 mL) ware added EDCI (536 mg, 2.80 mmol, 5.00 equiv) and HOBT (227 mg, 1.68 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1x5 mL), dried over anhydrous Na2SO4. After fdtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (80 mg, 94% purity) as a white solid. The crude was purified by reversed combi-flash chromatography and the pure fractions were concentrated and lyophilized to afford N-(2,2-difluoroethyl)-5-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl} pyridine-2-carboxamide (46 mg, 18%) as a white solid. LC-MS: (ES+H, m / zy. [M+H]+ =457.2. ’H NMR (400 MHz, DMSO-J6) 5 11.86 (s, 1H), 8.70 (t, 1H), 8.41 (s, 1H), 8.30 (d, 1H), 7.86 (d, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.41 (dd, 1H), 6.25 - 5.97 (m, 1H), 3.73 - 3.60 (m, 4H), 3.37 (s, 4H), 2.61 - 2.52 (m, 6H), 1.18 (t, 3H). The following examples were made using similar procedures shown for example 13. Ex NMR LCMS (ESI) m / z 40 XH NMR (400 MHz, DMSO-d6) 5 11.86 (s, 1H), 8.58 (t, 1H), 8.41 (d, 1H), 8.28 (d, 1H), 7.83 (d, 1H), 7.76 (s, 1H), 7.63 (d, 1H), 7.40 (dd, 1H), 3.77 -3.54 (m, 5H), 3.45 (dd, 1H), 3.45 - 3.26 (m, 4H), 3.26 (t, 2H), 2.59 - 2.51 (m, 7H), 1.95 - 1.82 (m, 1H), 1.58 (m, 1H), 1.26-1.16 (m, 3H) [M+H]+=477.35 41 1HNMR(300 MHz, DMSO-d6) 5 11.86 (s, 1H), 8.58 (t, 1H), 8.41 (d, 1H), 8.28 (d, 1H), 7.84 (d, 1H), 7.76 (s, 1H), 7.63 (d, 1H), 7.40 (dd, 1H), 3.78-3.54 (m, 5H), 3.45 (dd, 1H), 3.41-3.34 (m, 4H), 3.30-3.22 (m, 2H), 2.65-2.52 (m, 6H), 2.49-2.42 (m, 1H), 1.97-1.80 (m, 1H), 1.66-1.52 (m, 1H), 1.23-1.14 (m, 3H). [M+H]+=477.3 42 XH NMR (300 MHz, DMSO-d6) 5 11.86 (s, 1H), 8.45-8.25 (m, 3H), 7.84 (d, 1H), 7.77 (s, 1H),7.62 (s,lH), 7.40 (dd, 1H), 3.66 (s, 2H), 3.47-3.42 (m, 4H), 3.39-3.36 (m, 2H), 3.33-3.30 (m, 2H), 3.26 (s, 3H), 2.62-2.53 (m, 6H), 1.19 (t, 3H). [M+H]+=45L0 43 XHNMR (400 MHz, DMSO-d6) 5 11.86 (s, 1H), 8.41 (d, 1H), 8.27 (d, 1H), 8.08 (d, 1H), 7.83 (d, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.40 (dd, 1H), 4.13 - 4.00 (m, 1H), 3.66 (s, 2H), 3.35 - 3.32 (m, 4H), 2.60 - 2.51 (m, 6H), 1.26-1.13 (m, 9H) [M+H]+=434.9 44 Tf NMR (300 MHz, DMSO-d6) 5 11.86 (s, 1H), 8.41 (d,lH), 8.30 - 8.23 (m, 2H), 7.84 (d,lH), 7.76 (s, 1H), 7.63 (s, 1H), 7.41 (dd, 1H), 4.06-3.92 (m, 1H), 3.91 - 3.80 (m, 2H), 3.66 (s, 2H), 3.44 - 3.34 (m, 6H), 2.61 - 2.52 (m, 6H), 1.77- 1.57 (m, 4H), 1.19 (t, 3H). [M+H]+=477.20 45 1HNMR(300 MHz, DMSO-d6) 5 11.86 (s, 1H), 8.41 (d, 1H), 8.33 (d, 1H), 8.28 (d, 1H), 7.82 (d, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.40 (dd, 1H), 4.93 (s, [M+H]+=477.3 Ex NMR LCMS (ESI) m / z 1H), 4.02 (p, 1H), 3.66 (s, 2H), 3.35-3.33 (m, 4H) 2.64 - 2.53 (m, 6H), 2.25 - 2.39 (m, 2H), 2.19-2.01 (m, 2H), 1.28-1.11 (m, 6H). 46 ^NMR^OO MHz, DMS0-d6) 8 11.87 (s, 1H), 9.10 (d, 1H), 8.41 (s, 1H), 8.30 (d, 1H), 7.86 - 7.71 (m, 2H), 7.63 (s, 1H), 7.42 - 7.36 (m, 1H), 5.01 (q, 1H), 4.71 - 4.63 (m, 4H), 3.66 (s, 2H), 3.37-3.33 (m, 4H), 2.56 (m, 6H), 1.18 (t, 3H). [M+H]+=449.15 47 XHNMR (400 MHz, DMS0-d6) 8 11.85 (s, 1H), 8.40 (d, 1H), 8.36 (d, 1H), 8.27 (d, 1H), 7.83 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.40 (dd, 1H), 4.51 -4.40 (m, 1H), 3.89-3.78 (m, 2H), 3.74-3.68 (m, 1H), 3.65 (s, 2H), 3.60-3.54 (m, 1H), 3.39-3.35 (m, 4H), 2.60 - 2.52 (m, 6H), 2.19-2.09 (m, 1H), 1.99 -1.89 (m, 1H), 1.18 (t, 3H). [M+H]+=463.20 48 XHNMR (300 MHz, DMS0-d6) 8 11.87 (s, 1H), 8.45 - 8.33 (m, 2H), 8.28 (d, 1H), 7.84 (d, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.41 (dd, 1H), 4.45 (m, 1H), 3.92 - 3.78 (m, 2H), 3.78 - 3.65 (m, 1H), 3.66 (s, 2H), 3.57 (dd, 1H), 3.39 - 3.36 (m, 4H),2.58-2.54 (m, 6H), 2.24 - 2.06 (m, 1H), 2.02-1.86 (m, 1H), 1.19 (t, 3H). [M+H]+=463.30 49 1HNMR(300 MHz, DMS0-d6) 5 11.87 (s, 1H), 8.41 (s, 1H), 8.27 (s, 1H), 8.14 (d, 1H), 7.84 (d, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.41 (d, 1H), 4.82 (d, 1H), 4.01-3.96 (m, 2H), 3.66 (s, 2H), 3.33-3.29 (m, 4H), 2.57-2.54 (m, 6H), 2.06-1.92 (m, 1H), 1.91 - 1.77 (m, 1H), 1.70-1.58 (m, 2H), 1.53-1.37 (m, 2H), 1.19 (t, 3H). [M+H]+=477.20 50 'HNMR (300 MHz, DMS0-d6) 8 11.94 (s, 1H), 8.84 (t, 1H), 8.48 (s, 1H), 8.37 (d, 1H), 7.92 (d, 1H), 7.83 (s, 1H), 7.70 (s, 1H), 7.48 (dd, 1H), 3.73 (s, 2H), 3.58 (d, 2H), 3.43-3.40 (m, 4H), 2.85 (t, 2H), 2.64 (m, 6H), 1.26 (t, 3H). [M+H]+=445.90 52 XH NMR (400 MHz, DMSO-J6) 8 11.86 (s, 1H), 8.41 (d, 1H), 8.31 (d, 1H), 8.20 (t, 1H), 7.85 (d, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.41 (dd, 1H), 4.68 (s, 1H), 3.65 (s, 2H), 3.36 - 3.34 (m, 4H), 3.25 (d, 2H), 2.58 - 2.56 (m, 6H), 1.19 (t, 3H), 1.09 (s, 6H). [M+H]+=465.2 53 1HNMR(300 MHz, DMSO-J6) 8 11.87 (s, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 8.21 (d, 1H), 7.84 (d, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.41 (d, 1H), 3.93-3.87 (m, 1H), 3.76 - 3.63 (m, 4H), 3.40 -3.32 (m, 6H), 2.61 - 2.52 (m, 6H),1.87-1.83 (m, 1H), 1.75 - 1.49 (m, 3H), 1.19 (t, 3H). [M+H]+=477.3 54 XH NMR (300 MHz, DMSO-J6) 8 11.87 (s, 1H), 8.41 (s, 1H), 8.29 (d, 1H), 8.22 (d, 1H), 7.84 (d, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.41 (dd, 1H), 3.93-3.87 (m, 1H), 3.76 - 3.63 (m, 4H), 3.40 -3.32 (m, 6H), 2.61 - 2.52 (m, 6H), 1.871.83 (m, 1H), 1.77-1.51 (m, 3H), 1.18 (t, 3H). [M+H]+=477.3 55 1HNMR(400 MHz, DMS0-d6) 8 11.86 (s, 1H), 8.41 (d, 1H), 8.32 (d, 1H), 8.28 (d, 1H), 7.81 (d, 1H), 7.76 (t, 1H), 7.63 (d, 1H), 7.39 (dd, 1H), 4.92 (s, 1H), 4.02-3.96 (m, 1H), 3.66 (s, 2H), 3.36 - 3.33 (m, 4H), 2.61 - 2.52 (m, 6H), 2.37 - 2.24 (m, 2H), 2.14 - 2.02 (m, 2H), 1.24 (s, 3H), 1.18 (t, 3H). [M+H]+=477.35 56 1H NMR (300 MHz, DMS0-d6) 8 11.86 (s, 1H), 8.41 (d, 1H), 8.28 (d, 1H), 8.13 (d, 1H), 7.84 (d, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.41 (dd, 1H), 4.07 - 4.21 (m, 1H),3.45 (s, 2H), 3.70-3.62(m, 2H), 3.40-3.31 (m, 4H), 3.27 (s, 3H), 2.572.55 (m, 6H), 1.28 - 1.06 (m, 6H). [M+H]+=465.2 57 XH NMR (300 MHz, DMSO-d6) 8 11.87 (s, 1H), 8.41 (d, 1H), 8.34- 8.25 (m, 2H), 7.85 (d, 1H), 7.76 (s, 1H), 7.63 (d, 1H), 7.41 (dd, 1H), 4.84 (d, 1H), 3.85 - 3.71 (m, 1H), 3.66 (s, 2H), 3.40-3.16 (m, 1H) 3.34 - 3.27 (m, 4H), 3.21 -3.04 (m, 1H), 2.65 - 2.53 (m, 6H), 1.19 (t, 3H), 1.05 (d, 3H). [M+H]+=451.2 58 1HNMR(300 MHz, DMS0-d6) 8 11.87 (s, 1H), 8.92 (d, 1H), 8.41 (d, 1H), 8.28 (d, 1H), 7.82 (d, 1H), 7.76 (s, 1H), 7.63 (d, 1H), 7.39 (dd, 1H), 4.53 - [M+H]+=472.15 Ex NMR LCMS (ESI) m / z 4.46 (m, 1H), 3.66 (s, 2H),3.40 - 3.36 (m, 4H), 3.12 - 2.94 (m, 1H), 2.61 - 2.53 (m, 10H), 1.19 (t,3H). 59 XHNMR (400 MHz, DMSO-d6) 5 11.87 (s, 1H), 8.41 (d, 1H), 8.28 (d, 1H), 8.10 (d, 1H), 7.84 (d, 1H), 7.76 (s, 1H), 7.63 (d, 1H), 7.40 (dd, 1H), 4.85 (t, 1H), 3.99-3.95 (m, 1H), 3.65 (s, 2H), 3.46-3.40 (m, 2H), 3.34-3.45 (m, 4H) , 2.57 - 2.49 (m, 6H), 1.21 - 1.11 (m, 6H). [M+H]+=451.2 60 XH NMR (300 MHz, DMSO-J6) 5 11.84 (s, 1H), 8.41 (d, 1H), 8.33 - 8.22 (m, 2H), 7.84 (d, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.40 (dd, 1H), 3.65 (s, 2H), 3.50 -3.44 (m, 1H), 3.42 - 3.36 (m, 3H), 3.35 -3.29 (m, 3H), 3.28 (s, 3H), 2.59 -2.54 (m, 6H), 1.18 (t, 3H), 1.06 (d, 3H). [M+H]+=465.2 80 XH NMR (400 MHz, DMSO-d6) 5 11.86 (s, 1H), 8.51 (dd, 1H), 8.39 (d, 1H), 7.83 (d, 1H), 7.60 (d, 1H), 7.53 (t, 1H), 6.83 - 6.71 (m, 2H), 5.01 - 4.90 (m, 1H), 4.76 - 4.71 (m, 2H), 4.58 - 4.51 (m, 2H), 3.64 (s, 2H), 3.32 - 3.27 (m, 4H), 2.55-2.51 (m, 4H), 2.14 (d, 3H). 19F NMR (377 MHz, DMSO) 5-111.19. [M+H]+=452.05 81 Tf NMR (300 MHz, DMSO-d6) 5 11.97 (s, 1H), 9.15(d, 1H), 8.45(d, 2H), 7.78 (d, 1H), 7.62(d, 1H), 7.49 (d, 2H), 5.13-5.03 (m, 1H),4.79-4.46 (m, 4H), 3.71 (s, 2H), 3.51-3.42(m, 4H), 2.62 - 2.57 (m, 4H), 2.21- 2.08 (m, 1H), 0.91-0.90(m, 2H), 0.88 - 0.80 (m, 2H). [M+H]+=461.30 Example 14 Pd-coupling,CO / H2 step 1 step 3 step 4 Y=29.92% two steps Step 1: Preparation of tert-butyl 4-[2-formyl-6-(methylcarbamoyl)pyridin-3-yl]piperazine-l-carboxylate:

[00329] To a stirred solution of tert-butyl 4-[2-bromo-6-(methylcarbamoyl)pyridin-3-yl]piperazine-l-carboxylate (1.73 g, 4.33 mmol, 1.00 equiv) and TMEDA (604 mg, 5.20 mmol, 1.20 equiv) in toluene (60 ml) were added bis(adamantan-l-yl)(butyl)phosphane (311 mg, 0.87 mmol, 0.20 equiv) and Pd(OAc)2 (97 mg, 0.43 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 100 °C under CO / H2 atmosphere (1:1, 30atm). The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to afford tertbutyl 4-[2-formyl-6-(methylcarbamoyl)pyridin-3-yl]piperazine-l-carboxylate (1.50 g, crude) as a yellow solid. LC-MS: (ES-H, m / z): [M-H] = 346.8. Step 2: Preparation of tert-butyl 4-[2-(difluoromethyl)-6-(methylcarbamoyl)pyridin-3-yl]piperazine-l-carboxylate:

[00330] To a stirred solution of tert-butyl 4-[2-formyl-6-(methylcarbamoyl)pyridin-3-yl]piperazine-l-carboxylate (1.50 g, 4.29 mmol, 1.00 equiv) in DCM (8 mL) was added BAST (1.20 mL, 6.44 mmol, 1.50 equiv) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 4h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with ice-water (40 mL) at room temperature. The resulting mixture was extracted with CH2Q2 (3 x 40 mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-[2-(difluoromethyl)-6-(methylcarbamoyl)pyridin-3-yl]piperazine-l-carboxylate (580 mg, 36.05%, two steps) as an off-white solid. LC-MS: (ES+H, m / z): [M+H]+ = 371.1. ’H NMR(300 MHz, Chloroform-d) 5 8.29 (d, 1H), 7.94 (d, 1H), 7.63 (d, 1H), 7.21-6.80 (m, 1H), 3.69-3.61 (m, 4H), 3.06 (d, 3H), 3.03-2.98 (m, 4H), 1.51 (s, 9H). 19FNMR(282 MHz, CDC13) 5-116.99, Step 3: Preparation of 6-(difluoromethyl)-N-methyl-5-(piperazin-l-yl)pyridine-2-carboxamide, HC1 salt:

[00331] To a stirred solution of tert-butyl 4-[2-(difluoromethyl)-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (570 mg, 1.54 mmol, 1.00 equiv) was added HCl(gas)in 1,4-dioxane (4 mL, 4M) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 30min at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This resulted in 6-(difluoromethyl)-N-methyl-5-(piperazin-l-yl)pyridine-2-carboxamide, HC1 salt (610 mg, crude) as a red solid. LC-MS: (ES+H, m / z): [M+H]+ = 270.9. 1HNMR(300 MHz, DMSO-d6) 5 9.39 (s, 2H), 8.50-8.40 (m, 1H), 8.14 (d, 1H), 7.93 (d, 1H), 7.52-7.06 (m, 1H), 3.31-3.27 (m, 4H), 3.22-3.18 (m, 4H), 2.84 (d, 3H). Step 4: Preparation of 6-(difluoromethyl)-5-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl}-N-methylpyridine-2-carboxamide:

[00332] To a stirred solution of 6-(difluoromethyl)-N-methyl-5-(piperazin-l-yl)pyridine-2-carboxamide, HC1 salt (250 mg, 0.82 mmol, 1.40 equiv) and 7-(chloromethyl)-3-ethyl-lH-l,5-naphthyridin-2-one (130 mg, 0.58 mmol, 1.00 equiv) in MeCN (5 mL) were added DIEA (377 mg, 2.92 mmol, 5.00 equiv) and KI (2 mg, 0.01 mmol, 0.02 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for Ih at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (366 mg) was purified by Prep-HPLC to afford 6-(difluoromethyl)-5-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl}-N-methylpyridine-2-carboxamide (76.0 mg, 29.92%, two steps) as an off-white solid. LC-MS: (ES+H, m / z): [M+H]+= 457.2. 1HNMR(400 MHz, DMSO-d6) 5 11.86 (s, IH), 8.44-8.36 (m, 2H), 8.10 (d, IH), 7.86 (d, IH), 7.75 (s, IH), 7.62 (d, IH), 7.32-6.99 (m, IH), 3.68 (s, 2H), 3.06-2.98 (m, 4H), 2.83 (d, 3H), 2.66-2.53 (m, 6H), 1.22-1.15 (m, 3H). 19F NMR (377 MHz, DMSO) 5-115.95. Example 15 Step 1: Preparation of ethyl 2-bromo-2-cyclopropylacetate:

[00333] To a stirred solution of ethyl 2-cyclopropylacetate (10.00 g, 78.02 mmol, 1.00 equiv) in THF (100 mL) was added LDA (42.9 mL, 85.82 mmol, 1.10 equiv, 2.0 M in THF) dropwise at -78°C under nitrogen atmosphere. The reaction was stirred for 1 hour then TMSC1 (8.48 g, 78.02 mmol, 1.00 equiv) added dropwise and the reaction stirred for 3 hours as it warmed to room temperature. The reaction was cooled to -78 °C and NBS (15.28 g, 85.82 mmol, 1.10 equiv) in 50 mL THF added dropwise. The reaction was then stirred for 2 hours and allowed to warm to room temperature. The reaction was monitored by LCMS. The reaction was quenched by the addition of sat. NH4CI (aq.) (50 mL) at 0°C. The resulting mixture was extracted with Et2O (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed combi-flash chromatography to afford ethyl 2-bromo-2-cyclopropylacetate (5.00 g, 30.95%) as a yellow liquid. 'H NMR (300 MHz, Chloroform-d) 5 4.25 (q, 2H), 3.58 (d, 1H), 1.65 - 1.55 (m, 1H), 1.31 (t, 3H), 0.92 - 0.76 (m, 2H), 0.61 - 0.53 (m, 1H), 0.48 - 0.40 (m, 1H). Step 2: Preparation of ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate:

[00334] A solution of ethyl 2-bromo-2-cyclopropylacetate (5.00 g, 24.14 mmol, 1.00 equiv) and triethyl phosphite (5.22 g, 31.39 mmol, 1.30 equiv) was stirred for 24 hours at 130 °C under nitrogen atmosphere. The residue was purified by reversed combi-flash chromatography to afford ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate (2.40 g, 37.61%) as a yellow liquid. 1HNMR(300 MHz, Chloroform-d) 5 4.26 - 4.07 (m, 6H), 2.19 (dd, 1H), 1.30 (dt, 10H), 0.71 (dddd, 1H), 0.60 (ddddd, 1H), 0.47 - 0.37 (m, 1H), 0.24 (ddtd, 1H). Step 3: Preparation of methyl 6-[(lZ)-2-cyclopropyl-3-ethoxy-3-oxoprop-l-en-l-yl]-5-nitropyridine-3-carboxylate:

[00335] To a stirred mixture of NaH (0.29 g, 7.14 mmol, 1.50 equiv, 60%wt) in THF (20 mL) was added ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate (1.89 g, 7.14 mmol, 1.50 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 10 min at 0°C and then warmed to 40°C stirred for 10 min under nitrogen atmosphere. The resulting mixture was cooled to -78°C followed by the addition of methyl 6-formyl-5-nitropyridine-3-carboxylate (1.00 g, 4.76 mmol, 1.00 equiv) in THF (20 mL) dropwise. The resulting mixture was stirred for 30 min at -78°C under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of sat. NH4CI (aq.) (5 mL) at 0°C. The resulting mixture was added 20 mL water and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford methyl 6-[(lZ)-2-cyclopropyl-3-ethoxy-3-oxoprop-l-en-l-yl]-5-nitropyridine-3-carboxylate (700 mg, 45.93%) as a brown oil. LC-MS: (ES+H, m / zy [M+H]+=320.8. Step 4: Preparation of ethyl 7-cyclopropyl-6-oxo-5H-l,5-naphthyridine-3-carboxylate:

[00336] To a stirred mixture of methyl 6-[(lZ)-2-cyclopropyl-3-ethoxy-3-oxoprop-l-en-l-yl]-5-nitropyridine-3-carboxylate (600 mg, 1.87 mmol, 1.00 equiv) and Fe (1.04 g, 18.73 mmol, 10.00 equiv) in EtOH (10 mL) was added CaCL (1.24 g, 11.24 mmol, 6.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 90°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (2x50 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was added 50 mL water and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford ethyl 7-cyclopropyl-6-oxo-5H-l,5-naphthyridine-3-carboxylate (200 mg, 41.34%) as a yellow solid. LC-MS: (ES+H, m / zy. [M+H]+=259.0. Step 5: Preparation of 3-cyclopropyl-7-(hydroxymethyl)-lH-l,5-naphthyridin-2-one:

[00337] To a stirred solution of ethyl 7-cyclopropyl-6-oxo-5H-l,5-naphthyridine-3-carboxylate (160 mg, 0.62 mmol, 1.00 equiv) was added LiAlH4 (0.50 mL, 1.23 mmol, 2.00 equiv, 2.5M in THF) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0°C under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of IM aq HC1 (1 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 3-cyclopropyl-7-(hydroxymethyl)-lH-l,5-naphthyridin-2-one (100 mg, 74.65%) as a light yellow solid. LC-MS: (ES+H, m / zy. [M+H]+=217.2. Step 6: Preparation of 7-(chloromethyl)-3-cyclopropyl-lH-l,5-naphthyridin-2-one:

[00338] To a stirred mixture of 3-cyclopropyl-7-(hydroxymethyl)-lH-l,5-naphthyridin-2-one (80 mg, 0.37 mmol, 1.00 equiv) and DMF (3 mg, 0.04 mmol, 0.10 equiv) in DCM (10 mL) was added SOCI2 (264 mg, 2.22 mmol, 6.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to afford 7-(chloromethyl)-3-cyclopropyl-lH- l,5-naphthyridin-2-one as a yellow solid. The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m / z)'. [M+H]+=235.0. Step 7: Preparation of 5-{4-[(7-cyclopropyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl}-N-methylpyridine-2-carboxamide:

[00339] A mixture of 7-(chloromethyl)-3-cyclopropyl-lH-l,5-naphthyridin-2-one (80 mg, 0.34 mmol, 1.00 equiv), N-methyl-5-(piperazin-l-yl)pyridine-2-carboxamide (75 mg, 0.34 mmol, 1.00 equiv), KI (11 mg, 0.07 mmol, 0.20 equiv) and DIEA (220 mg, 1.71 mmol, 5.00 equiv) in MeCN (10 mL) was stirred for 2 hours at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL), and was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, to afford 5-{4-[(7-cyclopropyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl}-N-methylpyridine-2-carboxamide (85 mg, 58.57%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=419.3. 1HNMR(300 MHz, DMSO-J6) 5 11.89 (s, 1H), 8.43 - 8.36 (m, 2H), 8.26 (d, 1H), 7.83 (d, 1H), 7.61 (d, 1H), 7.44 - 7.35 (m, 2H), 3.64 (s, 2H), 3.34 - 3.28 (m, 4H), 2.78 (d, 3H), 2.56 (d, 4H), 2.21 - 2.07 (m, 1H), 0.97 (dt, 2H), 0.86 - 0.77 (m, 2H). Example 16 Step 1: Preparation of tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-l'(2'H)-carboxylate:

[00340] To a stirred mixture of 5-bromo-N-methylpyridine-2-carboxamide (300 mg, 1.40 mmol, 1.00 equiv) and tert-butyl 4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylate (518 mg, 1.67 mmol, 1.20 equiv) in l,4-dioxane / H2O (4 / 1,5 mL) were added Pd(dppf)C12 (102 mg, 0.14 mmol, 0.10 equiv) and K2CO3 (386 mg, 2.79 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-T(2'H)-carboxylate (330 mg, 74.53%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =318.2. Tf NMR (400 MHz, DMSO-d6) 5 8.75 - 8.67 (m, 2H), 8.04 - 7.95 (m, 2H), 6.41 (s, 1H), 4.08 - 4.00 (m, 2H), 3.56 (t, 2H), 2.82 (d, 3H), 2.53 (d, 2H), 1 43(s, 9H). Step 2: Preparation of tert-butyl 4-(6-(methylcarbamoyl)pyridin-3-yl)piperidine-l-carboxylate:

[00341] To a stirred solution of tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-l'(2'H)-carboxylate (330 mg, 1.04 mmol, 1.00 equiv) in methanol (20 mL) was added Pd / C (33 mg, 10%wt) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH (5x10 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 4-(6-(methylcarbamoyl)pyridin-3-yl)piperidine-l-carboxylate (320 mg, 96.36%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =320.2. XH NMR (400 MHz, DMSO-d6) 5 8.70 (d, 1H), 8.53 (d, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 4.09 (d, 2H), 2.81 (d, 6H), 1.78 (d, 2H), 1.55 (qd, 2H), 1.42 (s, 9H). Step 3: Preparation of N-methyl-5-(piperidin-4-yl)picolinamide, TFA salt:

[00342] To a stirred solution of tert-butyl 4-(6-(methylcarbamoyl)pyridin-3-yl)piperidine-l-carboxylate (310 mg, 0.97 mmol, 1.00 equiv) in DCM (5 mL) was added TFA (2 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for Ih at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product N-methyl-5-(piperidin-4-yl)picolinamide, TFA salt (510 mg, crude) was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+ =220.2. Step 4: Preparation of 5-(l-((7-ethyl-6-oxo-5,6-dihydro-l,5-naphthyridin-3-yl)methyl)piperidin-4-yl)-N-methylpicolinamide:

[00343] To a stirred mixture of N-methyl-5-(piperidin-4-yl)pyridine-2-carboxamide, TFA salt (294 mg, assumed 50% yield, 1.35 mmol, 2.00 eq) and 7-(chloromethyl)-3-ethyl-lH-l,5-naphthyridin-2-one (150 mg, 0.67 mmol, 1.00 equiv) in MeCN (3 mL) were added KI (112 mg, 0.67 mmol, 1.00 equiv) and DIEA (435 mg, 3.37 mmol, 5.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC. The pure fractions were concentrated and lyophilized to afford 5-{l-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperidin-4-yl}-N-methylpyridine-2-carboxamide (24.6 mg, 9.01%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =406.2. 1HNMR(400 MHz, DMSO-d6) 5 11.84 (s, IH), 8.69 (d, IH), 8.53 (d, IH), 8.40 (d, IH), 7.95 (d, IH), 7.86 (dd, IH), 7.75 (s, IH), 7.61 (s, IH), 3.62 (s, 2H), 2.94 (d, 2H), 2.81 (d, 3H), 2.68 (m, IH), 2.59 - 2.53 (m, 2H), 2.13 (m, 2H), 1.82 - 1.68 (m, 4H), 1.18 (t, 3H). Example 17 Preparation of tert-butyl 4-[2-cyano-4-(methoxycarbonyl)phenyl]piperazine-l-carboxylate:

[00344] To a stirred solution ofmethyl 4-bromo-3-cyanobenzoate (1.00 g, 4.17 mmol, 1.00 equiv) and tert-butyl piperazine-1-carboxylate (770 mg, 4.17 mmol, 1.00 equiv) in dioxane (10 mL) was added CS2CO3 (2.70 g, 8.33 mmol, 2.00 equiv) and RuPhos Palladacycle Gen.3 (350 mg, 0.42 mmol, 0.10 equiv) under nitrogen atmosphere. The resulting mixture was stirred overnight at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (5x100 ml). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-[2-cyano-4-(methoxycarbonyl)phenyl]piperazine-l-carboxylate (1.00 g, 69.50%) as a dark oil. LC-MS: (ES+H, m / z): [M+H-tBu]+ = 289.8. Tf NMR (400 MHz, Chloroform-J) 5 8.24 (d, 1H), 8.11 (dd, 1H), 6.97 (d, 1H), 3.91 (s, 3H), 3.68 -3.59 (m, 4H), 3.36-3.28 (m, 4H), 1.39 (s, 9H). Step 2: Preparation of tert-butyl 4-[2-cyano-4-(methylcarbamoyl)phenyl]piperazine-l-carboxylate:

[00345] To a stirred solution of tert-butyl 4-[2-cyano-4-(methoxycarbonyl)phenyl]piperazine-l-carboxylate (1.00 g, 2.90 mmol, 1.00 equiv) and methylamine (5 mL, 25%-30%wt in water) in methanol (5 mL). The resulting mixture was stirred overnight at 50°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-[2-cyano-4-(methylcarbamoyl)phenyl]piperazine-l-carboxylate (900 mg, 90.26%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H-tBu]+ =288.9. Tf NMR (300 MHz, Chloroform-J) 5 8.01 (d, 1H), 7.98 - 7.87 (m, 1H), 7.01 (d, 1H), 6.41 (s, 1H), 3.65 (t, 4H), 3.28 (t, 4H), 3.02 (d, 3H), 1.50 (s, 9H). Step 3: Preparation of 3-cyano-N-methyl-4-(piperazin-l-yl)benzamide, HC1 salt:

[00346] To a stirred solution of tert-butyl 4-[2-cyano-4-(methylcarbamoyl)phenyl]piperazine-l-carboxylate (900 mg, 2.61 mmol, 1.00 equiv) in Dichloromethane (3 mL) was added HCl(gas)in 1,4-dioxane (7 mL) dropwise at 0 °C. The resulting mixture was stirred for 3h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with N-hexane and ether (1:1) (12mlx3). The precipitated solids were collected by filtration and washed with ether (3x5 mL) to afford 3-cyano-N-methyl-4-(piperazin-l-yl)benzamide, HC1 salt (580 mg) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =244.9. Step 4: Preparation of 3-cyano-4-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl}-N-methylbenzamide:

[00347] To a stirred solution of 3-cyano-N-methyl-4-(piperazin-l-yl)benzamide, HC1 salt (150 mg, crude) and 7-(chloromethyl)-3-methyl-lH-l,5-naphthyridin-2-one (128 mg, 0.61 mmol, 1.00 equiv) in acetonitrile (8 mL) was added DIEA (238 mg, 1.84 mmol, 3.00 equiv) and KI (20 mg, 0.12 mmol, 0.20 equiv) under nitrogen atmosphere. The resulting mixture was stirred for 1.5h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The residue was purified by trituration with MeOH (3 mL). The resulting mixture was stirred for Ih at 50°C under nitrogen atmosphere. The precipitated solids were collected by filtration and washed with MeOH (2x1 mL). The pure fraction was concentrated under vacuum to afford 3-cyano-4-{4-[(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)methyl]piperazin-l-yl}-N-methylbenzamide (125.5 mg, 46.53%) as a white solid. LC-MS: (ES+H, m / z): [M-H]+ =431.30. 1H NMR (400 MHz, DMSO-J6) 5 11.87 (s, IH), 8.49 - 8.39 (m, 2H), 8.12 (d, IH), 8.01 (dd, IH), 7.75 (s, IH), 7.62 (s, IH), 7.19 (d, IH), 3.68 (s, 2H), 3.29 (m, 4H), 2.77 (d, 3H), 2.61 - 2.51 (m, 6H), 1.18 (t, 3H). Example 18 Step 1: Preparation of methyl 4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylate:

[00348] To a solution of methyl 4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate (480 mg, 1.97 mmol, 1.00 equiv) in MeOH / DCM (80 mL / 20 mL) was added Pd / C (200 mg, 10%wt) under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 2 days under hydrogen atmosphere. The reaction was monitored by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure. The residue was purified by reversed combi-flash chromatography to afford methyl 4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylate (170 mg, 35%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =246.2. Step 2: Preparation of 7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one:

[00349] To a stirred solution of methyl 4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylate (170 mg, 0.69 mmol, 1.00 equiv) in THF (8 mL) was added LiAlH4 (0.55 mL, 1.39 mmol, 2.00 equiv, 2.5M in THF) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 0°C under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of IM aq HC1 (10 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (150 mg, 100%) as a white solid. LC-MS: (ES+H, Wz): [M+H]+ =218.0. HNMR (400 MHz, DMSO-J6) 5 11.38 (s, 1H), 7.53 (d, 1H), 7.34 (s, 1H), 7.09 (dd, 1H), 5.40-5.36 (m, 1H), 4.79 (t, 2H), 4.56 (s, 2H), 3.03 (t, 2H). Step 3: Preparation of 7-(chloromethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one:

[00350] To a stirred solution of 7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (170 mg, 0.78 mmol, 1.00 equiv) and DMF (29 mg, 0.39 mmol, 0.50 equiv) in DCM (6 mL) was added thionyl chloride (744 mg, 6.26 mmol, 8.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to afford 7-(chloromethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (160 mg, 87%) as a white solid. LC-MS: (ES+H, Wz): [M+H]+=236.0. Step 4: Preparation of N-methyl-5-[4-({4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl}methyl)piperazin-l-yl]pyridine-2-carboxamide:

[00351] To a stirred solution of N-methyl-5-(piperazin-l-yl)pyridine-2-carboxamide (200 mg, crude) and DIEA (351 mg, 2.72 mmol, 4.00 equiv) in MeCN (6 mL) were added 7-(chloromethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (160 mg, 0.68 mmol, 1.00 equiv) and KI (22 mg, 0.14 mmol, 0.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The residue was purified by silica gel column chromatography to afford N-methyl-5-[4-({4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl}methyl)piperazin-l-yl]pyridine-2-carboxamide (56.5 mg, 19%) as a white solid. LC-MS: (ES+H, Wz): [M+H]+=420.1. 1HNMR(400 MHz, DMSO-J6) 5 11.36 (s, 1H), 8.40 (s, 1H), 8.27 (s, 1H), 7.83 (d, 1H), 7.56 (d, 1H), 7.43 - 7.28 (m, 2H), 7.16 (d, 1H), 4.79 (t, 2H), 3.60 (s, 2H), 3.43-3.31 (m, 4H), 3.05 (t, 2H), 2.84-2.73 (m, 3H), 2.61-2.52 (m, 4H). The following examples were made using similar procedures shown for example 18. Ex NMR LCMS (ESI) m / z 71 XH NMR (400 MHz, DMSO-d6) 5 11.37 (s, 1H), 8.27-8.12 (m, 2H), 8.568.19 (m, 4H), 4.79 (s, 2H), 3.65 - 3.61 (m, 2H), 3.53 - 3.35 (m, 4H), 3.13 -2.95 (m, 2H), 2.75 (d, 3H), 2.56 - 2.52 (m, 4H). 19F NMR (282 MHz, DMSO) 5 -120.38. [M+H]+=438.2 73 XHNMR (400 MHz, DMSO-d6) 5 11.46 - 11.36 (m, 1H), 8.37 - 8.26 (m, 2H), 7.90 - 7.83 (m, 1H), 7.56 - 7.06 (m, 4H), 4.92 (s, 2H), 3.72 - 3.55 (m, 2H), 3.30 - 3.16 (m, 4H), 3.10 - 2.95 (m, 2H), 2.70 - 2.52 (m, 4H). [M+H]+=423.2 Example 19 1: Preparation of 5-bromo-2-(l-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridine:

[00352] A solution of 5-bromo-2-(lH-imidazol-2-yl)pyridine (1.00 g, 4.46 mmol, 1.00 equiv) and NaH (0.23 g, 5.80 mmol, 1.30 equiv, 60%wt) in DMF (10 mL) was stirred for 0.5h at 0 °C, and then to the above solution was added SEMC1 (0.97 g, 5.80 mmol, 1.30 equiv) dropwise at room temperature. And the mixture was stirred for 2h. The reaction was monitored by LCMS. The reaction was quenched with water (50 ml) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3x50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 5-bromo-2-(l-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridine (1.20 g, 75.88%) as a brown oil. LC-MS: (ES+H, m / z): [M+H]+ =353.8 / 355.8. 'HNMR (300 MHz, Chloroform-d) 5 8.65 (d, 1H), 8.14 (d, 1H), 7.91 (d, 1H), 7.24 (d, 1H), 7.20 (d, 1H), 6.01 (s, 2H), 3.59 -3.53 (m, 2H), 0.93 - 0.87 (m, 2H), 0.00 (s, 9H). Step 2: Preparation of tert-butyl 4-[6-(l-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridin-3-yl]piperazine-l-carboxylate:

[00353] To a stirred solution of 5-bromo-2-(l-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridine (900 mg, 2.54 mmol, 1.00 equiv) and tert-butyl piperazine-1-carboxylate (426 mg, 2.29 mmol, 1.00 equiv) in dioxane (10 mL) was added RuPhos Palladacycle Gen.3 (118 mg, 0.25 mmol, 0.10 equiv) and CS2CO3 (1.66 g, 5.08 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred overnight at 100°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with CH2Q2 / MeOH (3:1) (5x100ml). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-[6-(l-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridin-3-yl]piperazine-l-carboxylate (900 mg, 77.08%) as an orange oil. LC-MS: (ES+H, m / z): [M+H]+ = 460.2. 1HNMR(400 MHz, Chloroform-d) 58.33 (d, 1H), 8.15 (d, 1H), 7.37 -7.34 (m, 1H), 7.24 (d, 1H), 7.21 (d, 1H), 6.08 (s, 2H), 3.74 -3.64 (m, 4H), 3.63 - 3.57 (m, 2H), 3.32 (t, 4H), 1.58 (s, 9H), 0.99 - 0.92 (m, 2H), 0.00 (s, 9H). Step 3: Preparation of l-[6-(l-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridin-3-yl]piperazine:

[00354] To a stirred solution of tert-butyl 4-[6-(l-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridin-3-yl]piperazine-l-carboxylate (1.00 g, 2.17 mmol, 1.00 equiv) and DIEA (5.62 g, 43.50 mmol, 20.00 equiv) in dioxane (20 mL) was added TMSOTf (4.84 g, 21.75 mmol, 10.00 equiv) dropwise at 0°C. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of MeOH (3mL) at room temperature. The residue was purified by silica gel column chromatography to afford 1 -[6-( 1 -{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridin-3-yl]piperazine (530 mg, 67.76%) as an orange oil. LC-MS: (ES+H, m / z): [M+H]+ = 360.2. 1HNMR(300 MHz, Chloroform-d) 58.26 (d, 1H), 8.09 -7.97 (m, 1H), 7.28 (d, 1H), 7.16 (d, 1H), 7.12 (d, 1H), 5.99 (s, 2H), 3.56 -3.46 (m, 2H), 3.35 - 3.26 (m, 4H), 3.15 -3.08 (m, 4H), 0.93 - 0.83 (m, 2H), 0.00 (s, 9H). Step 4: Preparation of 3-ethyl-7-({4-[6-(l-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridin-3-yl]piperazin-l-yl}methyl)-lH-l,5-naphthyridin-2-one:

[00355] To a stirred solution of l-[6-(l-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridin-3-yl]piperazine (160 mg, 0.44 mmol, 1.00 equiv) and 7-(chloromethyl)-3-ethyl-lH-l,5-naphthyridin-2-one (100 mg, 0.44 mmol, 1.00 equiv) in acetonitrile (8 mL) were added DIEA (172 mg, 1.34 mmol, 3.00 equiv) and potassium iodide (15 mg, 0.09 mmol, 0.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1.5 h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 3-ethyl-7-({4-[6-(l-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridin-3-yl]piperazin-l-yl}methyl)-lH-l,5-naphthyridin-2-one (300 mg, crude) as a brown solid. LC-MS: (ES+H, m / z): [M+H]+ = 546.0. Step 5: Preparation of 3-ethyl-7-({4-[6-(lH-imidazol-2-yl)pyridin-3-yl]piperazin-l-yl}methyl)-lH-l,5-naphthyridin-2-one:

[00356] To a stirred solution of 3-ethyl-7-({4-[6-(l-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridin-3-yl]piperazin-l-yl}methyl)-lH-l,5-naphthyridin-2-one (300 mg, 0.55 mmol, 1.00 equiv) in DCM (7 mL) was added TFA (3 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 3h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with ether (10mLx3). The residue was basified with NH4OH. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The pure fraction was concentrated under vacuum to afford 3-ethyl-7-({4-[6-(lH-imidazol-2-yl)pyridin-3-yl]piperazin-l-yl}methyl)-lH-l,5-naphthyridin-2-one (80.3 mg, 33.78%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ = 416.30. 1HNMR(300 MHz, DMSO-d6) 5 12.45 (s, 1H), 11.87 (s, 1H), 8.42 (d, 1H), 8.27 (d, 1H), 7.87 (d, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.44 (q, 1H), 7.05 (s, 2H), 3.66 (s, 2H), 3.34 (m, 4H), 2.59 - 2.51 (m, 6H), 1.23- 1.17 (t, 3H). Example 20 and Example 21 Step 1: Preparation of 7-ethyl-6-oxo-5H-l,5-naphthyridine-3-carboxylic acid:

[00357] To a solution of methyl 7-ethyl-6-oxo-5H-l,5-naphthyridine-3-carboxylate (1.15 g, 4.95 mmol, 1.00 equiv) in MeOH (15 mL) and H2O (3 mL) was added NaOH (0.59 g, 14.86 mmol, 3.00 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The residue was acidified to pH 4 with 6N HC1 (aq.). The resulting mixture was filtered, the solid was concentrated under reduced pressure to afford 7-ethyl-6-oxo-5H-l,5-naphthyridine-3-carboxylic acid (800.0 mg, crude) as a white solid. LC-MS: (ES+H, Wz): [M+H]+ = 218.9. 1HNMR(400 MHz, DMSO-J6) 5 13.43 (s, 1H), 12.08 (s, 1H), 8.89 (d, 1H), 8.15 (d, 1H), 7.82 (s, 1H), 2.62 -2.54(m, 2H), 1.20 (t, 3H). Step 2: Preparation of 7-ethyl-N-methoxy-N-methyl-6-oxo-5H-l,5-naphthyridine-3-carboxamide:

[00358] To a solution of 7-ethyl-6-oxo-5H-l,5-naphthyridine-3-carboxylic acid (800 mg, crude) and N,O-dimethylhydroxylamine (336 mg, 5.50 mmol, 1.50 equiv) in DMF (8 mL) was added EDCI (2.10 g, 11.00 mmol, 3.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 7-ethyl-N-methoxy-N-methyl-6-oxo-5H-l,5-naphthyridine-3-carboxamide (540 mg, 45.44%) as an off-white solid. LC-MS: (ES+H, Wz): [M+H]+ = 262.1. ‘H NMR (400 MHz, DMSO-J6) 5 12.02 (s, 1H), 8.64 (d, 1H), 7.89 (dd, 1H), 7.80 (s, 1H), 3.58 (s, 3H), 3.31(s, 3H), 2.57 (q, 2H), 1.20 (t, 3H). Step 3: Preparation of 7-acetyl-3-ethyl-lH-l,5-naphthyridin-2-one:

[00359] To a solution of 7-ethyl-N-methoxy-N-methyl-6-oxo-5H-l,5-naphthyridine-3-carboxamide (540 mg, 2.07 mmol, 1.00 equiv) in THF (5 mL) was added CH.MgBr (1.4 mL, 4.13 mmol, 2.00 equiv, 3M in THF) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1.5 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with water at 0°C. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 7-acetyl-3-ethyl-lH-l,5-naphthyridin-2-one (397 mg, 88.83%) as an off-white solid. LC-MS: (ES+H, m / z): [M+H]+ = 217.1. ^NMR (400 MHz, DMSO-J6) 5 12.06 (s, 1H), 8.98 (s, 1H), 8.09 (d, 1H), 7.84 (d, 1H), 2.67 (s, 3H), 2.58 (q, 2H), 1.20 (t, 3H). Step 4: Preparation of 3-ethyl-7-(l-hydroxyethyl)-lH-l,5-naphthyridin-2-one:

[00360] To a solution of 7-acetyl-3-ethyl-lH-l,5-naphthyridin-2-one (398 mg, 1.84 mmol, 1.00 equiv) in MeOH (5 mL) was added NaBH4 (174 mg, 4.59 mmol, 2.50 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with sat. NH4CI (aq.) at 0°C. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 3-ethyl-7-(l-hydroxyethyl)-lH-l,5-naphthyridin-2-one (335.0 mg, 83.60%) as a brown solid. LC-MS: (ES+H, m / zy [M+H]+ = 219.2. Step 5: Preparation of 7-(l-chloroethyl)-3-ethyl-lH-l,5-naphthyridin-2-one:

[00361] To a solution of 3-ethyl-7-(l-hydroxyethyl)-lH-l,5-naphthyridin-2-one (335 mg, 1.54 mmol, 1.00 equiv) in DCM (10 mL) was added SOCI2 (457 mg, 3.84 mmol, 2.50 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 4 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was used directly in the next step. LC-MS: (ES+H, m / zy [M+H]+ = 237.0. Step 6: Preparation of 5-{4-[l-(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)ethyl]piperazin-l-yl}-N-methylpyridine-2-carboxamide:

[00362] To a solution of 7-(l-chloroethyl)-3-ethyl-lH-l,5-naphthyridin-2-one (280 mg, 1.18 mmol, 1.00 equiv) and N-methyl-5-(piperazin-l-yl)pyridine-2-carboxamide (350 mg, crude) in MeCN (6 mL) was added KI (785 mg, 4.73 mmol, 4.00 equiv) and DIEA (917 mg, 7.10 mmol, 6.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 5-{4-[l-(7-ethyl-6-oxo-5H-l,5-naphthyridin-3-yl)ethyl]piperazin-l-yl}-N-methylpyridine-2-carboxamide (303.1 ...

Claims

1. A compound of Formula (III”), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:OFormula (III”), wherein:RC1 is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more RCa;each RCa is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;or two RCa on the same atom are taken together to form an oxo;RC2 is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, Q-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl;RC3 is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl;each R7 is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl;or two R7 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl;each R8 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;or two R8 on the same carbon are taken together to form an oxo;or two R8 on the same carbon, adjacent carbons, or opposite carbons are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl;n is 0-6;R12 is Ci-Cealkyl, Ci-Cedeuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl;each R11 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl;q is 0-3;each Ra is independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl;each Rb is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -nhch3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-c6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; andeach Rc and Rd are independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkyl(cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl;or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-C6hydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RC1 is halogen, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, cycloalkyl, or heterocycloalkyl.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RC1 is halogen, cycloalkyl, or heterocycloalkyl.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RC1 is halogen or cycloalkyl.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RC1 is halogen.

6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RC1 is cycloalkyl.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RC2 is hydrogen, deuterium, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RC2 is hydrogen, Ci-Cealkyl, or Ci-Cehaloalkyl.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RC2 is hydrogen.

10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RC2 is Ci-Cealkyl.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RC3 is hydrogen, deuterium, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RC3 is hydrogen, Ci-Cealkyl, or Ci-Cehaloalkyl.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RC3 is hydrogen or Ci-Cealkyl.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RC3 is hydrogen.

15. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,16. The compound of claim 1 or 15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein RC2         is17. The compound of claim 1 or 15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein RC2         is Cl18. The compound of claim 1 or 15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R7 is independently hydrogen, deuterium, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R7 is hydrogen.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R8 is Ci-Cealkyl; or two R8 on the same carbon are taken together to form an oxo.

22. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R8 on opposite carbons are taken together to form a cycloalkyl.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0-3.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 2.

25. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein nisi.

26. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R11 is independently deuterium, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cedeuteroalkyl.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R11 is independently halogen or Ci-Cealkyl.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R11 is independently halogen.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 0 or 1.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 1.

32. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 0.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R12 is Ci-Cealkyl or cycloalkyl.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R12 is Ci-Cealkyl.

35. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R12 is cycloalkyl.

36. The compound of claim 1, wherein the compound is selected from the group consisting of:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

37. The compound of claim 36, wherein the compound is:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

38. The compound of claim 36, wherein the compound is:Hor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

39. The compound of claim 36, wherein the compound is:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.H40. The compound of claim 36, wherein the compound is:     uor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

41. The compound of claim 36, wherein the compound is:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

42. The compound of claim 36, wherein the compound is:     Oor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

43. A pharmaceutical composition comprising a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

44. A method of treating cancer in a subject in need thereof, the method comprising administering a compound of any one of claims 1- 42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

45. The method of claim 44, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, a hematological cancer, gastrointestinal cancer, or lung cancer.

46. A method of treating a cancer comprising a BRCA1 and / or a BRCA2 mutation in a subject in need thereof, the method comprising administering a compound of any one of claims 1- 42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

47. The method of claim 46, wherein the cancer is bladder cancer, brain & CNS cancers, breast cancer, cervical cancer, colorectal cancer, esophagus cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cavity cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterus cancer.