Prolyl Hydroxylase Domain-Containing Protein (PHD) Inhibitors and Methods of Use Thereof

Abstract

Described herein are PHD inhibitors, and pharmaceutical compositions containing the inhibitors. The subject compounds and compositions are useful for treating inflammatory bowel disease.

Description

[Technical field]

[0001] This patent application claims the benefit of International Application No. PCT / CN2021 / 127023, filed October 28, 2021, and International Application No. PCT / CN2022 / 112270, filed August 12, 2022, which are incorporated by reference in their entireties. [Background technology]

[0002] Hypoxia-inducible factors (HIFs) mediate gene expression in response to changes in cellular oxygen concentration. HIFs are heterodimers with an oxygen-regulated subunit (HIF-α) and a constitutively expressed subunit (HIF-β). HIF prolyl hydroxylases, also known as prolyl hydroxylase domain-containing proteins (PHDs), exist in humans as three isoforms (PHD1, PHD2, and PHD3). PHDs function as oxygen sensors that orchestrate the hypoxia-inducible factor ("HIF") degradation pathway. In short, PHDs are responsible for the hydroxylation of HIFα, a subunit of HIF, initiating a pathway that ultimately leads to the degradation of HIFα by the proteasome. There are three subtypes of PHDs, including PHD1, PHD2, and PHD3. Inhibition of PHDs has been shown to be a promising treatment for HIFα-associated diseases, such as inflammatory bowel disease (IBD).

[0003] Inhibitors of PHDs modulate red blood cell production by inducing erythropoietin ("EPO") synthesis in both the kidney and liver, which stimulates the production of red blood cells in the bone marrow, and by regulating iron metabolism, an essential component of functional red blood cells. Inhibitors of PHDs may also suppress the production of hepcidin in the liver, which negatively impacts iron mobilization. It has also been speculated that inhibitors of PHDs may upregulate the expression of several iron metabolism genes, such as DMT1 and DCYTB. Because HIF prolyl hydrolases play a central role in cellular oxygen sensing, inhibitors of PHDs may be useful in the treatment of cardiovascular, metabolic, hematological, pulmonary, renal, hepatic, wound healing, and cancer, among others. Summary of the Invention

[0004] As used herein, the formula (I)

[0005] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, R 1 optionally independently one or more R 1a is a monocyclic heterocycloalkyl substituted with Each R 1a are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR bC(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same atom 1a come together to form oxo, X is N or CR 2 and R 2 is hydrogen, fluoro, chloro, bromo, -CN, -NO2, -OH, -OR a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R 3 are hydrogen, halogens, -CN, -NO2, -OH, -OR a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R 4 are hydrogen, halogens, -CN, -NO2, -OH, -OR a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Y is -O-, -S-, or -NR 6 - and R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; L is -(CR 7 R 8 ) p - and Each R 7 and R 8 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R on the same carbon 7 and R 8 taken together form a cycloalkyl or heterocycloalkyl, each of which optionally contains one or more R 7a is replaced by Each R 7a are independently halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; p is 0 to 4; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 9are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 9a is replaced by Or, two R on the same atom 9 come together to form oxo, Each R 9a are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NRc R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same atom 9a come together to form oxo, n is 0 to 4; Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Each R bare independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Each R c and R d is independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Or, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; and Each R is independently selected from halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or Disclosed are compounds, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R on the same atom are joined together to form oxo.

[0006] Also disclosed herein are pharmaceutical compositions comprising a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a pharma- ceutically acceptable excipient.

[0007] Also disclosed herein is a method of treating a disease or disorder in a subject, comprising administering to the subject a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein, wherein the disease or disorder is inflammatory bowel disease (IBD). In some embodiments of the methods disclosed herein, the disease or disorder is ulcerative colitis ("UC") or Crohn's disease ("CD").

[0008] Also disclosed herein is a method for stabilizing hypoxia-inducible factor (HIF) in a subject, comprising administering to the subject a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein. In some embodiments, the HIF is HIF-1α.

[0009] In some embodiments of the methods disclosed herein, the methods further comprise administration of an additional active agent.

[0010] Incorporation by Reference 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 PREFERRED EMBODIMENTS

[0011] definition In the following description, certain specific details are described to provide a thorough understanding of various embodiments. However, those 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 the description of the embodiments. Unless otherwise required by context, throughout the following specification and claims, the word "comprise" and its variations such as "comprises" and "comprising" should be interpreted in an open and inclusive sense, i.e., "including, but not limited to". Moreover, the headings provided herein are for convenience only and do not interpret the scope or meaning of the invention as set forth in the claims.

[0012] References throughout this specification to "some embodiments" or "embodiments" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. Thus, the phrases "in one embodiment" or "in an embodiment" appearing in various places throughout this specification do not necessarily all refer to the same embodiment. Moreover, 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 used in the sense of including "and / or" unless the content clearly dictates otherwise.

[0013] As used herein, the following terms have the following meanings unless otherwise indicated.

[0014] "oxo" refers to =O.

[0015] "Carboxyl" refers to --COOH.

[0016] "Cyano" refers to -CN.

[0017] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monoradical having from 1 to about 10 carbon atoms, more preferably from 1 to 6. 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-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-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, as well as longer alkyl groups such as, for example, heptyl, octyl, etc. Whenever appearing herein, a numerical range such as "C1-C6 alkyl" or "C1-6 alkyl" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also includes the use of the term "alkyl" without a numerical range specified. In some embodiments, alkyl is any of the C1- 10In some embodiments, the alkyl is a C1-6 alkyl. In some embodiments, the alkyl is a C1-5 alkyl. In some embodiments, the alkyl is a C1-4 alkyl. In some embodiments, the alkyl is a C1-3 alkyl. Unless otherwise specified herein, 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.

[0018] "Alkenyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans conformation about the double bond and is to 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 appearing herein, a numerical range such as "C2-C6 alkenyl" or "C2-6 alkenyl" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also includes the use of the term "alkenyl" where no numerical range is specified. Unless otherwise specifically stated herein, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkenyl is optionally substituted with halogen.

[0019] "Alkynyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadinyl, and the like. Whenever appearing herein, a numerical range such as "C2-C6 alkynyl" or "C2-6 alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also includes the use of the term "alkynyl" where no numerical range is specified. Unless otherwise specifically stated herein, 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.

[0020] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specified 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, etc. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkylene is optionally substituted with halogen.

[0021] "Alkoxy" means a group of the formula -OR a where R a is an alkyl group by definition. Unless otherwise specified 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, etc. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0022] "Aryl" refers to a group derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused ring system (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom), or a bridged ring system. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl groups include, but are not limited to, aryl groups derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene hydrocarbon ring systems. Unless otherwise specified herein, 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, etc. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with halogen.

[0023] "Cycloalkyl" refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, cycloalkyls are fully saturated. Representative cycloalkyls include aryls having 3 to 15 carbon atoms (e.g., C3-C4, C5-C6, C7-C8, C9-C10, C11-C12, C13-C14, C15-C16, C17-C18, C19-C20, C21-C22, C22-C30, C23-C31, C24-C25, C25-C32, C26-C27, C28-C33, C29-C34, C29-C35, C36-C37, C38-C39, C39-C41, C38-C42, C39-C43, C39-C44, C38-C45, C39-C46, C39-C47, C39-C48, C39-C49, C41-C41, C42-C43, C43-C44, C44-C45, C45-C46, C45-C47, C46-C48, C47-C48, C48-C49, C49-C49, C49-C51, C49-C52, C49-C53, C49-C54, C49-C55, C49-C56, C49-C57, C49-C58, C49-C59, C51-C61, C49-C51, C49-C52, C49-C5 15 Fully saturated cycloalkyl, or C3-C 15cycloalkenyl), 3 to 10 carbon atoms (e.g., C3-C 10 Fully saturated cycloalkyl, or C3-C 10Examples of cycloalkyl include, but are not limited to, cycloalkyls having 3 to 8 carbon atoms (e.g., C3-C8 fully saturated cycloalkyl, or C3-C8 cycloalkenyl), 3 to 6 carbon atoms (e.g., C3-C6 fully saturated cycloalkyl, or C3-C6 cycloalkenyl), 3 to 5 carbon atoms (e.g., C3-C5 fully saturated cycloalkyl, or C3-C5 cycloalkenyl), or 3 to 4 carbon atoms (e.g., C3-C4 fully saturated cycloalkyl, or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3 to 10 membered fully saturated cycloalkyl, or a 3 to 10 membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 to 6 membered fully saturated cycloalkyl, or a 3 to 6 membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 to 6 membered fully saturated cycloalkyl, or a 5 to 6 membered cycloalkenyl. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl include adamantyl, norbornyl, 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. Examples of partially saturated cycloalkyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated in the specification, cycloalkyl can be 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, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0024] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0025] "Haloalkyl" refers to an alkyl group, as defined above, that is substituted with one or more halo groups, as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0026] "Hydroxyalkyl" refers to an alkyl group, as defined above, substituted with 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 includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0027] "Aminoalkyl" refers to an alkyl group, as defined above, substituted with 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. Aminoalkyls include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0028] "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. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl is composed of 1-6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, where the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls include, for example, -CHOCH, -CHCHOCH, -CHCHOCHCHOCH, -CH(CH)OCH, -CHNHCH, -CHN(CH), -CHCHNHCH, or -CHCHN(CH). Unless otherwise specifically stated herein, a heteroalkyl is optionally substituted, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. 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, a heteroalkyl is optionally substituted with halogen.

[0029] "Heterocycloalkyl" refers to a 3-24 membered partially or fully saturated ring group containing 2-23 carbon atoms and 1-8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1-3 nitrogens. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, a heterocycloalkyl contains 1 nitrogen. In some embodiments, a heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless otherwise specified in the specification, a heterocycloalkyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused ring systems (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems, in which the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl group may be optionally oxidized, and the nitrogen atoms may be optionally quaternized. Representative heterocycloalkyl groups include those having 2 to 15 carbon atoms (e.g., C2-C 15 Fully saturated heterocycloalkyl or C2-C 15 heterocycloalkenyl), 2 to 10 carbon atoms (e.g., C2-C 10 Fully saturated heterocycloalkyl or C2-C 10heterocycloalkenyl), heterocycloalkyl having 2 to 8 carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl, or C2-C8 heterocycloalkenyl), heterocycloalkyl having 2 to 7 carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl, or C2-C7 heterocycloalkenyl), heterocycloalkyl having 2 to 6 carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl, or C2-C6 heterocycloalkenyl), heterocycloalkyl having 2 to 5 carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl, or C2-C5 heterocycloalkenyl), or heterocycloalkyl having 2 to 4 carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl, or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl groups include aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, and cycloalkyl groups. Examples of heterocycloalkyl include, but are not limited to, cycloalkyl, cycloalkyl-1,1-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dioxo-1,3-dioxol-4-yl, cycloalkyl-2-oxo-1,3-dioxol-4-yl, cycloalkyl-1,1 ...When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3-8 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-7 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-8 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-7 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-6 membered heterocycloalkenyl. Unless otherwise specifically stated herein, a heterocycloalkyl may be optionally substituted as described below, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heterocycloalkyl is optionally substituted with halogen.

[0030] "Heteroaryl" refers to a 5-14 membered ring system containing 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1-3 nitrogens. In some embodiments, the heteroaryl contains 1 or 2 nitrogens. In some embodiments, the heteroaryl contains 1 nitrogen. The heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused ring systems (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 group may be optionally oxidized, and the nitrogen atoms may be optionally quaternized. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a 5-6 membered heteroaryl. In some embodiments, the heteroaryl is a 6 membered heteroaryl. In some embodiments, the heteroaryl is a 5 membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, l), benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, Isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H -pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).Unless otherwise specified herein, 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, etc. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heteroaryl is optionally substituted with halogen.

[0031] The term "any" or "optionally" means that the event or circumstance described thereafter may or may not occur, and the description includes both cases where said event or circumstance occurs. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Furthermore, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art will understand that with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical and / or synthetically infeasible (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which are also defined as including optionally substituted alkyl groups, which may continue indefinitely). Thus, any of the described substituents should be understood to generally have a maximum molecular weight of up to about 1,000 daltons, more typically up to about 500 daltons.

[0032] The term "one or more" when referring to any substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0033] An "effective amount" or "therapeutically effective amount" refers to the amount of a compound administered to a mammalian subject, either in a single dose or as part of a series, that is effective to produce the desired therapeutic effect.

[0034] "Treatment" of an individual (e.g., a mammal such as a human) or cell is any type of intervention used to attempt to change the natural course of the individual or cell. In some embodiments, treatment includes administering a pharmaceutical composition after the initiation of a pathological event or after contact with a pathogen, and stabilizing the disease (e.g., the disease does not worsen) or relieving the disease.

[0035] compound Described herein are compounds of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, that are useful for the treatment of inflammatory bowel disease (IBD).

[0036] As used herein, the formula (I)

[0037] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, R 1is an optionally independently substituted monocyclic heterocycloalkyl; X is N or CR 2 and R 2 is hydrogen, fluoro, chloro, bromo, -CN, -NO2, -OH, -OR a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R 3 are hydrogen, halogens, -CN, -NO2, -OH, -OR a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R 4 are hydrogen, halogens, -CN, -NO2, -OH, -OR a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Y is -O-, -S-, or -NR 6 - and R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; L is -(CR 7 R 8 ) p - and Each R 7 and R 8 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R on the same carbon 7 and R 8 taken together form a cycloalkyl or heterocycloalkyl, each of which optionally contains one or more R 7a is replaced by Each R 7a are independently halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; p is 0 to 4; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 9 are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)Ra , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted; n is 0 to 4; Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted; Each R bare independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted; and Each R c and R d is independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted; Or, R c and R d Disclosed are compounds, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: together with the atom to which they are attached form an optionally substituted heterocycloalkyl.

[0038] As used herein, the formula (I)

[0039] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, R 1optionally independently one or more R 1a is a monocyclic heterocycloalkyl substituted with Each R 1a are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same atom 1a come together to form oxo, X is N or CR 2 and R 2 is hydrogen, fluoro, chloro, bromo, -CN, -NO2, -OH, -OR a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R 3 are hydrogen, halogens, -CN, -NO2, -OH, -OR a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R 4 are hydrogen, halogens, -CN, -NO2, -OH, -OR a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Y is -O-, -S-, or -NR 6 - and R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; L is -(CR 7 R 8 ) p - and Each R 7 and R 8 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R on the same carbon 7 and R 8taken together form a cycloalkyl or heterocycloalkyl, each of which optionally contains one or more R 7a is replaced by Each R 7a are independently halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; p is 0 to 4; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 9 are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 9a is replaced by Or, two R on the same atom 9 come together to form oxo, Each R 9a are independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same atom 9a come together to form oxo, n is 0 to 4; Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Each R b are independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; and Each R c and R d are independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently and optionally substituted with one or more R; Or, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; and Each R is independently selected from halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or Disclosed are compounds, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R on the same atom are joined together to form oxo.

[0040] In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, X is N. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, X is CR 2 It is.

[0041] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen, fluoro, or C1-C6 alkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen.

[0042] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is hydrogen.

[0043] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 4 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 4 is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 4 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 4 is hydrogen.

[0044] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5is C1-C6 alkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 5 is hydrogen.

[0045] In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof,

[0046] [ka] teeth,

[0047] [ka] It is.

[0048] In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof,

[0049] [ka] teeth,

[0050] [ka] It is.

[0051] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, Y is -O-, or -NR 6 In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, Y is -NR 6 In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, Y is -O-. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, Y is -S-.

[0052] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 6 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 6 is C1-C6 alkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 6 is hydrogen.

[0053] In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, p is 1 to 4. In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, p is 1 to 3. In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, p is 1 or 2. In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, p is 1. In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, p is 2. In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, p is 3.

[0054] In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R 7 and R 8 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl, or R 7 and R 8 In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R 7 and R 8is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. In some embodiments of a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 7 and R 8 In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R 7 and R 8 is independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R 7 and R 8 is hydrogen.

[0055] In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R 7a are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R 7 are independently halogen, -OH, -OR a or C1-C6 alkyl.

[0056] In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is aryl or heteroaryl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is phenyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is 5-membered heteroaryl or 6-membered heteroaryl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is 6-membered heteroaryl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, ring A is 6-membered pyridyl.

[0057] In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 1 to 3. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 2 to 4. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 2 or 3. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 1 or 2. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 0. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 1. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 2. In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, n is 3.

[0058] In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R 9are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0059] In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R 9 are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)OR b , C1-C6 alkyl, or C1-C6 haloalkyl.

[0060] In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R 9 are independently halogen or -CN.

[0061] In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R 9 is -CN.

[0062] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 may independently be one or more R 1a In some embodiments, R is a monocyclic heterocycloalkyl substituted with 1 can independently be one, two, three, or four R 1a In some embodiments, R 1 can be independently one or two R 1a In some embodiments, R 1is a substituted monocyclic heterocycloalkyl.

[0063] In some embodiments, R 1 is a 4-membered, optionally substituted monocyclic heterocycloalkyl. In some embodiments, R 1 is a 5-membered, optionally substituted monocyclic heterocycloalkyl. In some embodiments, R 1 is a 6-membered, optionally substituted monocyclic heterocycloalkyl. In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is R 1 In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 teeth,

[0064] [ka] each optionally containing one or more R 1a In some embodiments, R 1 teeth,

[0065] [ka] and optionally one or two R 1a In some embodiments, R 1 teeth,

[0066] [ka] and optionally one or two R 1a In some embodiments, R 1 teeth,

[0067] [ka] and optionally one or two R 1a In some embodiments, R 1 teeth,

[0068] [ka] and optionally one or two R 1a is replaced by.

[0069] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each of which is optionally independently selected from one or more R 1a is replaced by.

[0070] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 optionally, one or more R 1a and piperidinyl substituted with

[0071] In some embodiments, R 1 Optionally, independently, one or two R 1a In some embodiments, R is a monocyclic heterocycloalkyl substituted with 1 is optionally independently one or two R 1a and a 5-7 membered (eg, 6 membered) monocyclic heterocycloalkyl substituted with, where the monocyclic heterocycloalkyl contains 1 to 3 ring nitrogen atoms.

[0072] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is non-substitutive.

[0073] In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R1a are independently halogen, -CN, -OH, -OR a , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or two R on the same atom. 1a come together to form oxo.

[0074] In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R 1a are independently halogen, -CN, -OH, -OR a , -NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, or two R 1a come together to form oxo.

[0075] In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R 1aare independently halogen, -CN, -OH, -OR a , -NR c R d , -NR b C(=O)R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, or two R 1a come together to form oxo.

[0076] In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R 1a are independently halogen, -OH, -OR a , -NR b C(=O)R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, or cycloalkyl, or two R 1a come together to form oxo.

[0077] In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R 1a are independently C1-C6 alkyl (e.g., methyl), C1-C6 haloalkyl, or -C(=O)OR b (For example, -C(=O)O(C1-C6 alkyl)).

[0078] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1a is C(=O)NR c Rd In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1a is C(=O)NH2. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1a teeth,

[0079] [ka] It is.

[0080] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 teeth,

[0081] [ka]

[0082] [ka] It is.

[0083] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 teeth,

[0084] [ka]

[0085] [ka] It is.

[0086] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 teeth,

[0087] [ka] It is.

[0088] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 teeth,

[0089] [ka] It is.

[0090] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 teeth,

[0091] [ka] It is.

[0092] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R 1 teeth,

[0093] [ka] It is.

[0094] In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R ais independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl). In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R a is independently C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R ais independently C1-C6 alkyl.

[0095] In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently and optionally substituted with one or more R. In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl). In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R bis independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R b is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R b is independently hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R b In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R b is independently C1-C6 alkyl.

[0096] In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R c and R dis independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl). In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R c and R d is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R c and R d is independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R c and R d In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R c and R dis independently C1-C6 alkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R c is hydrogen, C1-C6 hydroxyalkyl, C1-C6 alkyl, C1-C6 aminoalkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R d is hydrogen, C1-C6 hydroxyalkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), or C1-C6 alkylene(heterocycloalkyl). In some embodiments of a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R d is -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2CH2OH, or -CH2CH2NHC(=O)Ot-butyl.

[0097] In some embodiments of the compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R.

[0098] In some embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R is independently halogen, -CN, -OH, -OC1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R is independently halogen, -CN, -OH, -OC1-C6 alkyl, -NH2, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, each R is independently halogen, -CN, -OH, -OC1-C6 alkyl, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl.

[0099] In some embodiments of the compounds disclosed herein, each R 1 , R 9 , R a , R b , R c , R d , R 7 and R 8 taken together, heterocycloalkyl formed by R c and R d When taken together, the heterocycloalkyl formed is optionally independently substituted with 1, 2, 3, or 4 substituents as defined herein. In some embodiments of the compounds disclosed herein, each R 1 , R 9 , R a , R b , R c , R d , R 7 and R8 taken together, heterocycloalkyl formed by R c and R d When taken together, the heterocycloalkyl formed is optionally substituted with one, two, or three substituents, independently as defined herein. In some embodiments of the compounds disclosed herein, each R 1 , R 9 , R a , R b , R c , R d , R 7 and R 8 taken together form a heterocycloalkyl, and R c and R d taken together form a heterocycloalkyl, which is optionally substituted with one or two substituents, independently as defined herein. In some embodiments of the compounds disclosed herein, each R 1 , R 9 , R a , R b , R c , R d , R 7 and R 8 taken together, heterocycloalkyl formed by R c and R d taken together form a heterocycloalkyl, which is optionally substituted independently with one substituent as defined herein.

[0100] In some embodiments of the compounds disclosed herein, R, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 7a , R 8 , R 9 , R 9a , R a , R b , R c , and / or R dThe abundance of deuterium in each of is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the total number of hydrogen and deuterium.

[0101] In some embodiments of the compounds disclosed herein, R, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 7a , R 8 , R 9 , R 9a , R a , R b , R c and / or R d One or more of the groups contains deuterium at a percentage higher than the natural abundance of deuterium.

[0102] In some embodiments of the compounds disclosed herein, one or more hydrogens are selected from the following groups: R, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 7a , R 8 , R 9 , R 9a , R a , R b , R c and / or R d is replaced with one or more deuterium at one or more of

[0103] In some embodiments of the compounds disclosed herein, one or more hydrogens in ring A are replaced with one or more deuteriums.

[0104] All combinations of the groups described above for the various variables are contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one of skill in the art to provide stable moieties and compounds.

[0105] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is one of the compounds in Table 1.

[0106] [Table 1-1]

[0107] [Table 1-2]

[0108] [Table 1-3]

[0109] [Table 1-4]

[0110] [Table 1-5]

[0111] [Table 1-6]

[0112] [Table 1-7]

[0113] [Table 1-8]

[0114] [Table 1-9]

[0115] [Table 1-10]

[0116] [Table 1-11]

[0117] [Table 1-12]

[0118] [Table 1-13]

[0119] [Table 1-14]

[0120] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein contain one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers, and their corresponding mixtures. In some circumstances, the compounds described herein have one or more chiral centers, and each center exists in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric and epiisomeric forms, and their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers resulting from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers of the compound 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, separable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubility, 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 on differences in solubility. In some embodiments, the optically pure enantiomers are then recovered along with the resolving agent by any practical means that does not result in racemization.

[0121] labeled compound In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease 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 listed herein except for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, e.g., 2 H(D), 3 H(T), 13 C. 14 C. l5 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Compounds described herein, and pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, that contain the above-mentioned isomers and / or other isomers of other atoms, are within the scope of the present invention. Compounds described herein, and pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, that contain the above-mentioned isomers and / or other isomers of other atoms, are within the scope of the present invention. Certain isotopically labeled compounds, e.g. 3 H and 14 Those in which a radioactive isotope, such as C, is incorporated are useful in drug and / or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred for their ease of preparation and detectability.

[0122] In some embodiments, the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the total number of hydrogen and deuterium. In some embodiments, one or more of the substituents disclosed herein contain deuterium at a rate higher than the natural abundance of deuterium. In some embodiments, one or more hydrogens are replaced with one or more deuteriums in one or more of the substituents disclosed herein.

[0123] 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.

[0124] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0125] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with any of a number of inorganic or organic bases, as well as inorganic and organic acids, to form pharma- ceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or their solvates or stereoisomers, or by separately reacting the purified compounds in their free form with the appropriate acid or base and isolating the salt thus formed.

[0126] Examples of pharma- ceutically acceptable salts include salts prepared by reaction of the compounds described herein with an inorganic, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, dihydrogen chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, bromide, etc. Hydrogen salts include hydroiodide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, 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, tosylate, undecanoate, and xylenesulfonate.

[0127] Additionally, the compounds described herein can be prepared by dissolving the free base form of the compounds in an aqueous solution of inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, as well 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, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzylsulfonic acid, phenyl ... The amines may be prepared as pharma- ceutically acceptable salts formed by reacting with pharma- ceutically acceptable inorganic or organic acids, including, but not limited to, organic acids such as benzenesulfonic 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 acid, are used in the preparation of salts that are not themselves pharma- ceutically acceptable but are useful as intermediates in obtaining the compounds disclosed herein, their solvates, or stereoisomers, and their pharma- ceutically acceptable acid addition salts.

[0128] In some embodiments, compounds described herein that contain free acid groups are reacted with a suitable base, such as hydroxides, carbonates, bicarbonates, sulfates, ammonia, or pharma- ceutically acceptable organic primary, secondary, tertiary, or quaternary amines of pharma- ceutically acceptable metal cations. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, and aluminum salts. Specific examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl)4, etc.

[0129] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It will be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

[0130] solvate In some embodiments, the compounds described herein exist as solvates. The present invention provides a method of treating a disease by administering such a solvate. The present invention further provides a method of treating a disease by administering such a solvate as a pharmaceutical composition.

[0131] Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments are formed during the process of crystallization with pharma- ceutically acceptable solvents such as water, ethanol, etc. 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 process described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization 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 and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0132] Tautomers In some circumstances, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by the movement of a hydrogen atom, with a switch of a single bond and an adjacent double bond. In bond configurations where tautomerization is possible, chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0133] Treatment Disclosed herein is a method of treating a disease or disorder in a subject, comprising administering to the subject a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein the disease or disorder is inflammatory bowel disease (IBD). In some embodiments, the disease or disorder is ulcerative colitis ("UC") or Crohn's disease ("CD"). In some embodiments, the disease or disorder is ulcerative colitis ("UC"). In some embodiments, the disease or disorder is Crohn's disease ("CD").

[0134] Inflammatory bowel disease (IBD) IBD is an umbrella term used to describe diseases involving chronic inflammation of the digestive tract. Types of IBD include ulcerative colitis ("UC"), and Crohn's disease ("CD"). IBD symptoms vary and depend on the severity and location of the inflammation. According to GlobalData, in 2019, there were 1.7 million patients diagnosed with UC across eight major markets (US, 5 EU, Japan, Canada), with market sales reaching $6.8 billion that year. [In addition, there were 1.3 million people already diagnosed with UC across eight major markets (US, 5 EU, Japan, Canada), with market sales reaching $7.4 billion.]

[0135] Inflammatory bowel disease is characterized by repeated mucosal inflammation and injury, and loss of intestinal epithelial barrier function, leading to the passage of bacteria or bacterial products from the intestinal lumen to the serosa and blood, resulting in systemic bacteremia and endotoxemia. PHD inhibition has been shown to reduce disease severity at several levels of clinical scoring in a mouse model of colitis. The proposed mechanism of therapeutic activity of PHD inhibitors is through stabilization of HIF-1α, promoting epithelial barrier enhancement and healing.

[0136] PHD inhibitors may be a new treatment option for IBD and may be more effective when combined with available anti-inflammatory drugs.

[0137] Administration In certain embodiments, compositions containing the compound(s) described herein are administered for prophylactic and / or therapeutic treatment. 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 symptom of the disease or condition. Amounts effective for this use will vary depending on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drug, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0138] In prophylactic applications, compositions containing the compounds described herein are administered to patients susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose." In this use, the exact amount will also vary depending on the patient's health status, weight, and the like. When used in patients, the effective amount for this use will vary depending on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatment involves administering a pharmaceutical composition containing a compound described herein or a pharma- ceutically acceptable salt thereof to a mammal that has previously experienced and is currently in remission from at least one symptom or risk factor of the disease being treated, in order to prevent the return of symptoms of the disease or condition.

[0139] In certain embodiments where the patient's disease does not improve, at the physician's discretion, administration of the compound is administered chronically, i.e., for an extended period of time, including for the patient's lifetime, to ameliorate or otherwise control or limit the symptoms of the patient's disease or disorder.

[0140] In certain embodiments where the patient's condition improves, the dose of the administered drug is temporarily reduced or temporarily suspended for a certain period 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 the drug holiday is, by way of example only, between 10% and 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%.

[0141] Once the patient's disease has improved, a maintenance dose is administered as needed. In specific embodiments, the dosage or frequency of administration, or both, are then reduced as a function of symptoms to a level at which the improved disease, disorder, or condition is maintained. In certain embodiments, however, the patient requires intermittent or daily treatment for an extended period of time upon any recurrence of symptoms.

[0142] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined by the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0143] In general, however, the doses used for adult human treatment typically range from 0.01 mg to 5000 mg per day. In one aspect, the doses used for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example, two, three, four or more subdoses per day.

[0144] In one embodiment, a suitable daily dosage for the compounds described herein or pharma- ceutically acceptable salts thereof is about 0.01 to about 50 mg / kg body weight. In some embodiments, the daily dosage, or the amount of active substance in the dosage form, is less than or greater than the ranges indicated herein, depending on many variables related to the individual treatment regimen. In various embodiments, the daily dosage and unit dosage will vary depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the physician's judgment.

[0145] The toxicity and therapeutic efficacy of such treatment regimens are 10 and ED 90The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD is the dose ratio between toxic and therapeutic effects. 50 and ED 50 In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating a therapeutically effective daily dosage range and / or a therapeutically effective unit dosage for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is sufficient to achieve an ED with minimal toxicity. 50 In certain embodiments, the daily dose range and / or unit dose varies within this range depending upon the dosage form employed and the route of administration utilized.

[0146] Any of the foregoing aspects are further embodiments in which the compound described herein, or a pharma- ceutically acceptable salt thereof, is (a) administered systemically to the mammal, and / or (b) administered orally to the mammal, and / or (c) administered intravenously 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.

[0147] Any of the foregoing aspects are further embodiments that include a single administration of an effective amount of the compound, including further embodiments where (i) the compound is administered once daily, or (ii) the compound is administered to the mammal multiple times over the course of a day.

[0148] Any of the above aspects are further embodiments that include multiple administrations of an effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in the case of a single administration, (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 includes a drug holiday during which administration of the compound is temporarily suspended or the dose of the compound administered is temporarily reduced, and at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0149] Route of administration Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.Further, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0150] In certain embodiments, the compounds described herein are administered in a local rather than systemic manner, for example, by injecting the compound directly into an organ, often in a depot preparation or sustained release formulation. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome targets the organ and is taken up selectively by the organ. In still other embodiments, the compounds described herein are provided in the form of a rapid release formulation, in the form of a sustained release formulation, or in the form of an intermediate release formulation. In still other embodiments, the compounds described herein are administered locally.

[0151] Pharmaceutical Compositions / Formulations The compounds described herein are administered to subjects in need thereof in a pharmaceutical composition, either alone or in combination with pharma- ceutically acceptable carriers, excipients, or diluents, according to standard pharmaceutical practice.In one embodiment, the compounds may be administered to animals.The compounds may be administered orally or parenterally, including intravenously, intramuscularly, intraperitoneally, subcutaneously, rectally, and topically.

[0152] In another aspect, the present disclosure provides a pharmaceutical composition comprising the compound described herein, or its pharmaceutically acceptable salt, solvate or stereoisomer, and at least one pharmaceutically acceptable excipient.The pharmaceutical composition is formulated in a conventional manner, using one or more pharmaceutically acceptable excipients that facilitate the processing of active compound into pharmaceutically usable preparations.The appropriate formulation varies according to the route of administration selected. Summary summaries 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, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated by reference herein for such disclosures.

[0153] In some embodiments, the pharma- ceutically acceptable excipient is selected from a carrier, a binder, a filler, a suspending agent, a flavoring agent, a sweetening agent, a disintegrant, a dispersing agent, a surfactant, a lubricant, a coloring agent, a diluent, a solubilizing agent, a wetting agent, a plasticizer, a stabilizer, a permeation enhancer, a humectant, an antifoaming agent, an antioxidant, a preservative, and any combination thereof.

[0154] The pharmaceutical compositions described herein are administered to a subject by a suitable route of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. 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 dissolving formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and immediate and controlled release mixed formulations.

[0155] Pharmaceutical compositions containing a compound described herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, are manufactured in a conventional manner, such as, by way of example only, by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or compressing processes.

[0156] Pharmaceutical compositions for oral use can be obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, adding suitable auxiliary agents as necessary, and then processing the granulated mixture 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 corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If necessary, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, are added. In some embodiments, dyes or pigments are added to the coating of tablets or dragees to identify or characterize different dose combinations of active compounds.

[0157] Orally administered pharmaceutical compositions include push-fit capsules made of gelatin and soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules contain the active ingredient in a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound is dissolved or suspended in a suitable liquid such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. In some embodiments, stabilizers are added.

[0158] Pharmaceutical compositions for parenteral use are formulated as injections or infusions. In some embodiments, pharmaceutical compositions suitable for injection or infusion include sterile aqueous solutions or dispersions or sterile powders containing the compounds described herein, or their pharma- ceutically acceptable salts, solvates, or stereoisomers. In some embodiments, pharmaceutical compositions include liquid carriers. In some embodiments, liquid carriers are solvents or liquid dispersion media, including, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and any combination thereof. In some embodiments, pharmaceutical compositions further include preservatives to prevent the growth of microorganisms.

[0159] Use in combination Disclosed herein are methods of treating inflammatory bowel disease (IBD) using a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0160] In some embodiments, the additional therapeutic agent is administered simultaneously with 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 to administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound disclosed herein.

[0161] In some embodiments, the additional therapeutic agent includes cardiovascular agents such as calcium channel blockers, including amlodipine, clevidipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, and verapamil; statins, including atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin; fibrates, including gemfibrozil and fenofibrate; acebutolol, atenolol, betaxolol, bisoprolol, beta-blockers including benazepril, carvedilol, esmolol, labetalometoprolol, nadolol, nebivolol, penbutolol, propranolol, sotalol, and timolol; ACE inhibitors including benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and tondolapril; platelet aggregation inhibitors such as aspirin, cangrelor, clopidogrel, cilostazol, dipyridamole, prasugrel, and ticagrelor.

[0162] In some embodiments, the additional therapeutic agent is an agent for treating a metabolic disorder. These agents include pancreatic lipase inhibitors (e.g., orlistat), insulin, biguanides (e.g., buformin, metformin, and phenformin), and insulin sensitizers including the glitazones (e.g., pioglitazone and rosiglitazone), sulfonylureas (e.g., acetohexamide, chlorpropamide, tolazamide, tolbutamide, gliclazide, glimepiride, glipizide, and glyburide), and meglitinides (e.g., nategly, catecholamines ... These include insulin secretagogues including serotonin-releasing hormone (serotonin-releasing hormone, serotonin-releasing hormone, and repaglinide), α-glucosidase inhibitors (e.g., acarbose and miglitol), glucagon-like peptide analogs and agonists (e.g., exenatide, liraglutide, and taspoglutide), dipeptidyl peptidase-4 inhibitors (e.g., alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin), and amylin analogs (e.g., pramlintide).

[0163] In some embodiments, the additional therapeutic agent is an agent for treating a wound healing disorder, hi some embodiments, the additional therapeutic agent is an anti-inflammatory agent, an analgesic agent, an antipruritic agent, or an anti-infective agent.

[0164] Examples of anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids.Representative NSAIDs include apazone, aspirin, celecoxib, diclofenac (with and without misoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid sodium, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, choline and magnesium salicylate, salsalate, and sulindac.Representative corticosteroids include betamethasone, cortisone acetate, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone. Representative analgesics include acetaminophen sulfate and morphine sulfate, as well as codeine, hydrocodone, oxycodone, propoxyphene, and tramadol, all with or without acetaminophen. Representative antipruritic agents for systemic use include cyproheptadine, diphenhydramine, gabapentin, hydroxyzine, and ondansetron.

[0165] Representative antipruritic agents for topical use include ammonium lactate, benzocaine, calamine, capsaicin, clioquinol, crotamiton, diphenhydramine, doxepin, hydrocortisone, lidocaine, menthol, methyl salicylate, and pramoxine.

[0166] Examples of anti-infective agents include antibacterial agents, antifungal agents, and antiviral agents.

[0167] Representative antibacterial agents include aminoglycosides such as amikacin, gentamicin, kanamycin, neomycin, paromomycin, and tobramycin; carbapenems such as doripenem, ertapenem, imipenem, and meropenem; cephalosporins in combination with β-lactamase inhibitors such as ceftazidime / avibactam and ceftolozane / tazobactam; first generation cephalosporins such as cefadroxil, cefazolin, cephalexin, and cephradine; cefotetan, cefprozil, cefuroxime, efoxitin, and loxacin; second-generation cephalosporins such as lacarbef; third-generation cephalosporins such as cefdinir, cefditoren, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, and ceftriaxone; fourth-generation and next-generation cephalosporins such as cefepime and ceftaroline; glycopeptide antibiotics such as dalbavancin, oritavancin, telavancin, and vancomycin; glycylcyclines such as tigecycline; and lincomycins such as clindamycin. and their derivatives, macrolides such as azithromycin, clarithromycin, erythromycin, and fidaxomicin, and macrolide derivatives including ketolides such as telithromycin, oxazolidinone antibiotics such as linezolid and tedizolid, penicillins including aminopenicillins such as amoxicillin, ampicillin, antipseudomonas penicillins such as carbenicillin, piperacillin, and ticarcillin, amoxicillin / clavulanate, ampicillin / sulbactam, piperacillin / tazobactam, and ticarcillin penicillins with beta-lactamase inhibitors such as penicillin / clavulanate; natural penicillins such as penicillin G benzathine, penicillin V potassium, and procaine penicillin; penicillinase-resistant penicillins such as dicloxacillin, nafcillin, and oxacillin; quinolones such as cinoxacin, ciprofloxacin, delafloxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, and trovafloxacin;Sulfonamides such as sulfamethoxazole / trimethoprim, and sulfisoxazole, tetracyclines and their derivatives such as demeclocycline, doxycycline, doxycycline / omega-3 polyunsaturated fatty acids, doxycycline / salicylic acid, minocycline, and oxytetracycline. Other representative antibacterial agents include atovaquone, aztreonam, bacitracin, chloramphenicol, colitimethate, dalfopristin / quinupristin, daptomycin, erythromycin / sulfisoxazole, fosfomycin, metronidazole, pentamidine, rifaximin, spectinomycin, and trimetrexate.

[0168] Representative antifungal agents include azole antifungal agents such as clotrimazole, fluconazole, isavuconazonium, itraconazole, ketoconazole, miconazole, posaconazole, and voriconazole, echinocandins such as anidulafungin, caspofungin, and micafungin, and polyenes such as amphotericin B, amphotericin B cholesteryl sulfate, amphotericin B lipid complex, and nystatin. Other representative antifungal agents include flucytosine, griseofulvin, and terbinafine.

[0169] Representative antiviral agents include purine nucleosides such as acyclovir, cidofovir, famciclovir, ganciclovir, ribavirin, valacyclovir, and valganciclovir.

[0170] In some embodiments, the additional therapeutic agent is an anti-cancer agent.In some embodiments, the additional therapeutic agent is a chemotherapeutic agent (i.e., cytotoxic or anti-tumor agent), such as alkylating agents, antibiotics, antimetabolites, plant-derived drugs, and topoisomerase inhibitors, as well as a molecular targeting agent that prevents cancer growth and metastasis by interfering with certain molecules involved in tumor growth and progression.Molecular targeting agents include both small molecule agents and biologics.

[0171] Representative alkylating agents include bischloroethylamines (nitrogen mustards), including chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, and uracil mustard; aziridines, including thiotepa; alkylalkone sulfonates, including busulfan; nitrosoureas, including carmustine, lomustine, and streptozocin; non-classical alkylating agents, including altretamine, dacarbazine, and procarbazine; and platinum compounds, such as carboplatin, cisplatin, nedaplatin, oxaliplatin, satraplatin, triplatin tetranitrate, and the like.

[0172] Representative antibiotics include anthracyclines, including aclarubicin, amrubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, barbicin, and zorubicin; anthracenediones, including mitoxantrone and pixantrone; and streptomycins, including actinomycin, bleomycin, dactinomycin, mitomycin C, plicamycin.

[0173] Representative antimetabolites include dihydrofolate reductase inhibitors including aminopterin, methotrexate, and pemetrexed, thymidylate synthase inhibitors including raltitrexed and pemetrexed, folinic acid including leucovorin, adenosine deaminase inhibitors including pentostatin, halogenated / ribonucleotide reductase inhibitors including cladribine, clofarabine, and fludarabine, thiopurines including thioguanine and mercaptopurine, thymidylate synthase inhibitors including fluorouracil, capecitabine, tegafur, carmofur, and floxuridine, DNA polymerase inhibitors including cytarabine, ribonucleotide reductase inhibitors including gemcitabine, hypomethylating agents including azacitidine and decitabine, ribonucleotide enzyme reduction inhibitors including hydroxyurea, and asparagine depleting agents including asparaginase.

[0174] Representative type I topoisomerase inhibitors include camptothecins, including belotecan, irinotecan, rubitecan, and topotecan.

[0175] Representative type II topoisomerase inhibitors include epipodophyllotoxin derivatives such as amsacrine, etoposide, etoposide phosphate, and teniposide.

[0176] Molecular targeted therapies include biologics such as cytokines and other immunomodulatory agents. Useful cytokines include interleukin-2 (IL-2, aldesleukin), interleukin-4 (IL-4), interleukin-12 (IL-12), and interferons, which include over 23 related subtypes. Other cytokines include granulocyte colony-stimulating factor (CSF) (filgrastim), and granulocyte macrophage CSF (sargramostim). Other immunomodulatory agents include bacillus Calmette-Guerin, levamisole, and monoclonal antibodies against tumor antigens such as octreotide, trastruzumab, and rituximab, as well as cancer vaccines that induce an immune response against tumors.

[0177] In addition, molecular targeted agents that inhibit specific molecules involved in tumor growth and progression include inhibitors of epidermal growth factor (EGF), transforming growth factor-α (TGF a), TGFp, heregulin, insulin-like growth factor (IGF), fibroblast growth factor (FGF), keratinocyte growth factor (KGF), colony-stimulating factor (CSF), erythropoietin (EPO), interleukin-2 (IL-2), nerve growth factor (NGF), platelet-derived growth factor (PDGF), stem cell growth factor (HGF), vascular endothelial growth factor (VEGF), angiopoietin, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), HER4, insulin-like growth factor 1 receptor (IGF1R), IGF2R, fibroblast growth factor 1 receptor (FGF1R), FGF2R, FGF3R, FGF4R, vascular endothelial growth factor receptor (VEGFR), immune These include tyrosine kinase with globulin-like and epidermal growth factor-like domains 2 (Tie-2), platelet-derived growth factor receptor (PDGFR), Abl, Bcr-Abl, Raf, FMS-like tyrosine kinase 3 (FLT3), c-Kit, Src, protein kinase c (PKC), tropomyosin receptor kinase (Trk), Ret, mammalian target of rapamycin (mTOR), Aurora kinase, polo-like kinase (PLK), mitogen-activated protein kinase (MEK), mesenchymal-epithelial transition factor (c-MET), cyclin-dependent kinase (CDK), Akt, extracellular signal-regulated kinase (ERK), and poly(ADP) ribose polymerase (PARP).

[0178] Specific molecular targeted agents include selective estrogen receptor modulators such as tamoxifen, toremifene, fulvestrant, and raloxifene, antiandrogens such as bicalutamide, nilutamide, megestrol, and flutamide, and aromatase inhibitors such as exemestane, anastrozole, and letrozole.Specific molecular targeted agents include selective estrogen receptor modulators such as tamoxifen, toremifene, fulvestrant, and raloxifene, antiandrogens such as bicalutamide, nilutamide, megestrol, and flutamide, and aromatase inhibitors such as exemestane, anastrozole, and letrozole. EXAMPLES

[0179] Intermediate A: Synthesis of methyl 2-chloro-5-hydroxy-1,7-naphthyridine-6-carboxylate

[0180] [ka] Step 1: To a mixture of methyl (E)-3-aminobut-2-enoate (10 g, 87 mmol) in MeOH (100 mL) was added methyl prop-2-ynoate (7.78 g, 92.6 mmol). The mixture was stirred at 70° C. for 12 h. The mixture was cooled to 5° C. The precipitate was filtered and triturated with MTBE (50 mL×3). Methyl 6-hydroxy-2-methylnicotinate (5 g, 34% yield) was obtained as a white solid. 1 H NMR(400MHz,CDCl3)δ12.61(s,1H),8.02(d,J=8Hz,1H),6.42(d,J=12Hz,1H),3.84(s,3H),2.72(s,3H).

[0181] Step 2: A mixture of methyl-6-hydroxy-2-methylnicotinate (5 g, 29.8 mmol) in POCl3 (17.7 g, 115 mmol) was stirred at 100° C. for 4 h. The reaction was slowly poured into ice water (100 mL) and then extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with NaHCO3 (50 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was used directly in the next step.

[0182] Step 3: To a solution of methyl-6-chloro-2-methylnicotinate (6 g, 32.4 mmol) in CCl4 (60 mL) was added NBS (6.9 g, 38.7 mmol), and BPO (1.56 g, 6.45 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with DCM (60 mL) and washed with H2O (60 mL x 3). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give methyl 2-(bromomethyl)-6-chloronicotinate as a yellow solid (11 g, crude). LCMS: RT = 0.981 min, MS m / z (ESI) [M+H] + =264.1.

[0183] Step 4: To a solution of 2-(bromomethyl)-6-chloronicotinate (5 g, 18.9 mmol) and methyl 2-(p-tolylsulfonylamino)acetate (4.6 g, 18.9 mmol) in DMF (50 mL) was added K2CO3 (5.02 g, 47.4 mmol) and NaI (0.28 g, 1.86 mmol). The mixture was stirred at 50 °C under N2 atmosphere for 12 h. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with H2O (80 mL x 3). The organic layer was washed with brine (80 mL x 3), dried over MgSO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give methyl 6-chloro-2-(((N-(2-methoxy-2-oxoethyl)-4-methylphenyl)sulfonamido)methyl)nicotinate (6 g, crude product) as a yellow solid.

[0184] Step 5: To a solution of methyl 6-chloro-2-(((N-(2-methoxy-2-oxoethyl)-4-methylphenyl)sulfonamido)methyl)nicotinate (6 g, 14 mmol) in DMSO (60 mL) was added K2CO3 (11.6 g, 84.3 mmol). The mixture was stirred at 50 °C under N2 atmosphere for 4 h. The mixture was diluted with H2O (60 mL) and the aqueous solution was adjusted to pH 6 with 1 M HCl. The precipitated solid was filtered and dried to give intermediate A (1.5 g, 45% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ8.86(s,1H),8.72(d,J=0.9Hz,1H),7.91(d,J=8.8Hz,1H),3.95(s,3H).

[0185] General Procedure A: Synthesis of tert-butyl 4-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)piperazine-1-carboxylate (Example 29)

[0186] [ka] Step 1: To a solution of intermediate A (1 g, 4.19 mmol) in MeOH (30 mL) was added 5-(aminomethyl)pyridine-2-carbonitrile (0.84 g, 6.29 mmol), TEA (2.91 mL, 20.95 mmol) and the reaction was stirred overnight at 75° C. The reaction mixture was filtered through a regular funnel, the filter cake was washed with 10 mL of MeOH and dried in vacuum to give intermediate B, 2-chloro-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide (1.1 g, 3.24 mmol, 77% yield) as a yellow solid.

[0187] Step 2: To a solution of intermediate B (1.1 g, 3.24 mmol) in DMSO (15 mL) was added TEA (1.35 mL, 9.71 mmol), tert-butyl piperazine-1-carboxylate (904 mg, 4.86 mmol) and the reaction was stirred at 100 °C under N for 2 h. The reaction was cooled and poured into water H2O (200 mL). The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated NaCl solution (30 mL x 3) and concentrated in vacuo. The residue was triturated with CH3CN (20 mL) and CH2Cl2 (5 mL) and filtered to give Example 29 (500 mg, 1.02 mmol, 32% yield) as a white solid. LCMS: RT = 1.838 min, MS m / z (ESI) [M+H] + =490.1. 1 H NMR(400MHz,DMSO-d6)δ13.36(s,1H),9.77(t,J=6.3Hz,1H),8.76(s,1H),8.44(s,1H),8.29(d,J=9.4Hz,1H), 8.00(s,2H),7.48(d,J=9.5Hz,1H),4.63(d,J=6.3Hz,2H),3.82-3.79(m,4H),3.50-3.48(m,4H),1.46(s,9H).

[0188] General Procedure C: Synthesis of N-(2-chloro-4-cyanobenzyl)-5-hydroxy-2-morpholino-1,7-naphthyridine-6-carboxamide (Example 3)

[0189] [ka] Step 1: To a mixture of intermediate A (300 mg, 1.26 mmol) and morpholine (76.67 mg, 880.03 μmol, 77.44 μL) in THF (10 mL) was added DIEA (324.96 mg, 2.51 mmol, 437.95 μL) at 25° C. The mixture was stirred at 50° C. for 17 h. Morpholine (76.67 mg, 880.03 μmol, 77.44 μL) was added and the mixture was stirred at 65° C. for 4.5 h. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give methyl 5-hydroxy-2-morpholino-1,7-naphthyridine-6-carboxylate (128 mg, 383.84 μmol, 31% yield) as a white solid. LCMS: RT=0.637 min, MS m / z (ESI) [M+H] + =290.1.

[0190] Step 2: To a solution of methyl 5-hydroxy-2-morpholino-1,7-naphthyridine-6-carboxylate (128 mg, 442.47 μmol) in THF (1.5 mL) and HO (1.5 mL) was added LiOH·HO (37.14 mg, 884.94 μmol) at 25 °C. The mixture was stirred at 25 °C for 16 h and at 50 °C for an additional 3 h. The reaction mixture was concentrated and adjusted to pH = 6 with HCl (1 M). Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL × 3). The aqueous solution was lyophilized to give 5-hydroxy-2-morpholino-1,7-naphthyridine-6-carboxylic acid (130 mg, crude) as a yellow solid. LCMS: RT = 0.525 min, MS m / z (ESI) [M+H] + =276.1.

[0191] Step 3: To a mixture of carboxylic acid (45 mg, 163.48 μmol) and TEA (49.63 mg, 490.45 μmol, 68.26 μL) in DMF (1 mL) was added HATU (68.38 mg, 179.83 μmol) at 25° C. The mixture was stirred at 25° C. for 1 h. Then, amine (32.68 mg, 196.18 μmol) was added and the mixture was stirred at 25° C. for 2 h. Two drops of water were added. The mixture was filtered. The filtrate was purified by preparative HPLC and lyophilized to give the product, which was combined with another batch of product (6.0 mg) and lyophilized to give Example 3 (10.78 mg, 25.15 μmol, 6% yield) as a white solid. LCMS: RT=0.831 min, MS m / z (ESI) [M+H] + =424.1. 1 H NMR(400MHz,DMSO-d6)δ=13.31 (s,1H),9.76-9.68(m,1H),8.47(s,1H),8.29(d,J=9.6Hz,1H),8.08(d,J=1.6Hz,1 H),7.85-7.76(m,1H),7.55-7.46(m,2H),4.63(d,J=6.4Hz,2H),3.80-3.70(m,8H).

[0192] General Procedure D: Synthesis of N-(2-chloro-4-cyanobenzyl)-5-hydroxy-2-(piperazin-1-yl)-1,7-naphthyridine-6-carboxamide (Example 5)

[0193] [ka] Step 1: To a solution of intermediate A (500 mg, 2.10 mmol) and tert-butyl piperazine-1-carboxylate (467.5 mg, 2.52 mmol) in anhydrous DMSO (5 mL) was added TEA (525 mg, 5.25 mmol). The solution was stirred under N2 at 100 °C for 16 h. The reaction mixture was poured into H2O (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography. Methyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-hydroxy-1,7-naphthyridine-6-carboxylate (200 mg, 25% yield) was obtained as a yellow solid. LCMS: RT = 1.002 min, MS m / z (ESI) [M+H] + =389.0.

[0194] Step 2: To a solution of methyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-hydroxy-1,7-naphthyridine-6-carboxylate (100 mg, 0.295 mmol) and 4-(aminomethyl)-3-chlorobenzonitrile (60 mg, 0.359 mmol) in anhydrous MeOH (1.5 mL) was added TEA (60 mg, 0.594 mmol). The solution was stirred at 75° C. under N2 for 20 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product (150 mg, crude, yellow oil) was directly taken into the next step without further purification. LCMS: RT=1.097 min, MS m / z (ESI) [M+H] + =523.4.

[0195] Step 3: To a solution of the crude product (150.0 mg, 0.287 mmol) in ethyl acetate (1.5 mL) was added a solution of 4N HCl / EtOAc (0.4 mL, 1.435 mmol). The solution was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by preparative HPLC to give Example 5 (25.4 mg, 21% yield) as a white solid. LCMS: RT=2.217 min, MS m / z (ESI) [M+H] + =423.2. 1 H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.41(s,1H),8.41-8.23(m,2H),8.07-8.06(m,1H),7.8 1-7.79(m,1H),7.51-7.49(m,2H),4.63-4.62(m,2H),3.75-3.72(m,4H),2.83-2.80(m,4H). General Procedure F: Synthesis of N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(3-methoxypropanamido)-1,7-naphthyridine-6-carboxamide

[0196] [ka] To a solution of intermediate B (80 mg, 0.24 mmol) in NMP (2 mL) was added 3-methoxypropanamide (48.56 mg, 0.47 mmol), Xantphos (27.25 mg, 0.05 mmol), Pd2(dba)3 (21.56 mg, 0.02 mmol), and K3PO4 (149.95 mg, 0.71 mmol) and the reaction was stirred under N2 in a microwave reactor at 150 °C for 1 h. The reaction mixture was poured into saturated NaCl (100 mL) and extracted with EA (40 mL x 3). The organic layer was dried over Na2SO4, filtered to separate the organic layer and concentrated in vacuo. The residue was purified using preparative HPLC eluting with MeCN into water (0.1% FA) to give the title compound (36.81 mg, 39%). LCMS: 407.4 [M+H] + , 1H NMR(400MHz,DMSO-d6)δ13.55(s,1H),11.13(s,1H),9.87(s,1H),8.78(s,1H),8.64-8.60(m,3H),8. 01(d,J=1.3Hz,2H),4.68(d,J=6.3Hz,2H),3.66(t,J=6.1Hz,2H),3.26(s,3H),2.75(t,J=6.1Hz,2H).

[0197] Example 6: Synthesis of (R)-N-(2-chloro-4-cyanobenzyl)-5-hydroxy-2-(3-hydroxypyrrolidin-1-yl)-1,7-naphthyridine-6-carboxamide

[0198] [ka] To a solution of intermediate A (100 mg, 0.42 mmol) and (R)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine (126 mg, 0.63 mmol) in anhydrous DMSO (30 mL) was added TEA (106 mg, 1.06 mmol). The solution was stirred at 100° C. for 16 h. The reaction mixture was diluted with HO ( The mixture was poured into a 100 ml hexanes flask (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography. Methyl (R)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-5-hydroxy-1,7-naphthyridine-6-carboxylate (110 mg, 65% yield) was obtained as a yellow solid. LCMS: RT=1.179 min, MS m / z (ESI)[M+H] + =404.3.

[0199] To a solution of methyl (R)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-5-hydroxy-1,7-naphthyridine-6-carboxylate (100 mg, 0.25 mmol) and 4-(aminomethyl)-3-chlorobenzonitrile (50.0 mg, 0.30 mmol) in anhydrous MeOH (1.5 mL) was added TEA (50 mg, 0.50 mmol). The solution was stirred at 75° C. under N2 atmosphere for 20 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product (140 mg, yellow oil) was directly taken into the next step without further purification. LCMS: RT=1.099 min, MS m / z (ESI) [M+H] + =538.4.

[0200] To a solution of (R)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-N-(2-chloro-4-cyanobenzyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide (140 mg, 0.26 mmol) in ethyl acetate (1.5 mL) was added a solution of 4N HCl in ethyl acetate (0.35 mL, 1.30 mmol). The solution was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by preparative HPLC to give Example 6 (13.3 mg, 12% yield) as a white solid. LCMS: RT=2.472 min, MS m / z (ESI) [M+H] + =424.2. 1 H NMR(400MHz,CDCl3)δ12.66(s,1H),8.47(s,1H),8.46-8.31(m,2H),7.70-7.69(m,1H ),7.58-7.56(m,2H),6.99(s,1H),4.80-4.70(m,3H),3.74(s,4H),2.21-2.18(m,2H).

[0201] Example 22: Synthesis of N-((6-carbamoylpyridin-3-yl)methyl)-5-hydroxy-2-morpholino-1,7-naphthyridine-6-carboxamide

[0202] [ka] To a solution of N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-morpholino-1,7-naphthyridine-6-carboxamide (120 mg, 0.31 mmol) in anhydrous MeOH (2 mL) was added 3M NaOH solution (3 mL). The mixture was stirred at room temperature under N2 for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give Example 22 (8.5 mg, 7% yield) as a white solid. LCMS: RT=0.890 min, MS m / z (ESI) [M+H] + =409.3. 1 H NMR(400MHz,DMSO-d6)δ13.47(s,1H),9.74(s,1H),8.59(d,J=1.6Hz,1H),8.38(s,1H),8.25(d,J=9.4Hz,1H),8.05(s,1H),7.97 (d,J=8.0Hz,1H),7.89(dd,J=8.1,2.0Hz,1H),7.56(s,1H),7.43(d,J=10.0Hz,1H),4.57(d,J=6.3Hz,2H),3.70(d,J=5.5Hz,8H).

[0203] Example 24: Synthesis of 5-((5-hydroxy-2-morpholino-1,7-naphthyridine-6-carboxamido)methyl)picolinic acid

[0204] [ka] To a solution of N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-morpholino-1,7-naphthyridine-6-carboxamide (120 mg, 0.3 mmol) in anhydrous MeOH (2 mL) was added 3M aqueous NaOH (3 ml). The solution was stirred under N2 at 70° C. for 20 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give Example 24 (37 mg, 30% yield) as a yellow solid. LCMS: RT=1.962 min, MS m / z (ESI) [M+H] + =410.4, 1H NMR(400MHz,DMSO-d6)δ13.45(s,1H),9.73(s,1H),8.66(s,1H),8.39(s,1H),8.25(d,J=9.4Hz ,1H),7.93(dd,J=38.0,7.9Hz,2H),7.44(d,J=9.4Hz,1H),4.58(s,2H),3.70(d,J=6.7Hz,8H).

[0205] Example 41: Synthesis of (S)-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(3-(piperazine-1-carbonyl)pyrrolidin-1-yl)-1,7-naphthyridine-6-carboxamide

[0206] [ka] To a solution of intermediate B (150 mg, 0.44 mmol) in DMSO (2 mL) was added TEA (0.245 mL, 1.77 mmol), methyl (3S)-pyrrolidine-3-carboxylate hydrochloride (95 mg, 0.57 mmol) and the reaction was stirred at 100° C. for 3 h. The reaction was purified by preparative HPLC to give methyl (S)-1-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)pyrrolidine-3-carboxylate (120 mg, 0.28 mmol, 63% yield) as a white solid. LCMS: RT=1.102 min, MS m / z (ESI) [M+H] + =433.3.

[0207] To a solution of methyl (S)-1-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)pyrrolidine-3-carboxylate (100 mg, 0.23 mmol) in THF (0.5 mL) was added TFA (2 mL) and the reaction was stirred at room temperature for 48 h. The reaction was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The organic layer was separated, washed with saturated NaCl solution, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with methanol (0-10%) to chloroform (0-10%) to give (S)-1-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)pyrrolidine-3-carboxylic acid (85 mg, 0.20 mmol, 88% yield) as a white solid. LCMS: RT=0.912 min, MS m / z (ESI) [M+H] + =419.1.

[0208] To a solution of (S)-1-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)pyrrolidine-3-carboxylic acid (80 mg, 0.19 mmol) in DMF (2 mL) was added tert-butyl piperazine-1-carboxylate (46 mg, 0.25 mmol), HATU (109 mg, 0.29 mmol), TEA (0.080 mL, 0.57 mmol) and the reaction was stirred at room temperature for 3 h. The mixture was added HO (15 mL) and extracted with tert-butyl methyl ether (10 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give tert-butyl (S)-4-(1-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)pyrrolidine-3-carbonyl)piperazine-1-carboxylate (80 mg, 0.14 mmol, 71% yield) as a white solid. LCMS: RT=1.009 min, MS m / z (ESI) [M+H] + =587.2.

[0209] To a solution of tert-butyl (S)-4-(1-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)pyrrolidine-3-carbonyl)piperazine-1-carboxylate (75 mg, 0.13 mmol) in FA (4 mL) was added and the reaction was stirred at room temperature for 2 h. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC to give Example 41 (6.86 mg, 0.01 mmol, 11% yield) as a white solid. LCMS: RT=1.296 min, MS m / z (ESI) [M+H] + =487.2. 1 H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.42(s,1H),8.26(d,J=9.1Hz,2H),8.00(d,J=1.2Hz,2H),7.14(d, J=9.3Hz,1H),4.63(s,2H),3.85-3.54(m,9H),2.82-2.80(m,2H),2.75-2.73(m,2H),2.20-2.15(m,2H).

[0210] Example 45: Synthesis of (R)-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(3-(hydroxymethyl)-4-methylpiperazin-1-yl)-1,7-naphthyridine-6-carboxamide

[0211] [ka] To a solution of intermediate B (200 mg, 0.59 mmol) in DMSO (2 mL), TEA (0.41 mL, 2.95 mmol) and tert-butyl (2R)-2-(hydroxymethyl)piperazine-1-carboxylate (191.41 mg, 0.89 mmol) were added and the reaction was stirred at 100° C. under N2 for 2 h. The reaction was cooled and poured into water H2O (200 mL). The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography (0-50% ethyl acetate in petroleum) to give tert-butyl (R)-4-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (206 mg, 0.40 mmol, 67% yield) as an off-white solid. LCMS: RT=0.888 min, MS m / z (ESI) [M+H] + =520.0.

[0212] To a solution of tert-butyl (R)-4-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (50 mg, 0.10 mmol) in DCM (0.5 mL) was added TFA (0.5 mL, 6.73 mmol) and the reaction was stirred at room temperature for 1 h. The reaction was concentrated in vacuo and dried to give (R)-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(3-(hydroxymethyl)piperazin-1-yl)-1,7-naphthyridin-6-carboxamide (50 mg, 0.09 mmol, 94% yield) as a yellow oil. LCMS: RT=0.695 min, MS m / z (ESI) [M+H] + =420.0.

[0213] To a solution of (R)-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(3-(hydroxymethyl)piperazin-1-yl)-1,7-naphthyridine-6-carboxamide (40 mg, 0.1 mmol) in DCE (5 mL) was added sodium bis(acetyloxy)boranyl acetate (80.5 mg, 0.4 mmol) and formaldehyde (4.3 mg, 0.1 mmol) and the reaction was stirred at room temperature for 16 h. The reaction was concentrated in vacuo and purified by preparative HPLC to give Example 45 (5.37 mg, 0.012 mmol, 13% yield) as a red solid. LCMS: RT=0.870 min, MS m / z (ESI) [M+H] + =434.0. 1 H NMR(400MHz,DMSO-d6)δ13.35(s,1H),9.78-9.76(m,1H),8.76(s,1H),8.43(s,1H),8.28(d,J=9.2Hz,1H),8.14(s,1H),8.00(s,2H) ,7.48(d,J=9.5Hz,1H),4.85-4.84(m,1H),4.65-4.63(m,2H),4.59-4.24(m,4H),3.72-3.70(m,3H),3.00-2.92(m,3H),2.35(s,3H).

[0214] Example 46: Synthesis of (R)-2-(4-acetyl-3-(hydroxymethyl)piperazin-1-yl)-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide

[0215] [ka] To a solution of (R)-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(3-(hydroxymethyl)piperazin-1-yl)-1,7-naphthyridine-6-carboxamide (20 mg, 0.05 mmol) in DCM (1 mL) was added TEA (0.066 mL, 0.48 mmol) and acetyl chloride (0.003 mL, 0.04 mmol) and the reaction was stirred at room temperature for 3 h. The reaction was concentrated in vacuo and purified by preparative HPLC to give Example 46 (6.60 mg, 0.014 mmol, 30% yield) as a white solid. LCMS: RT=0.964 min; MS m / z (ESI) [M+H] + =462.0. 1 H NMR(400MHz,DMSO-d6)δ13.37(s,1H),9.85-9.82(m,1H),8.76(s,1H),8.41(s,1H),8.29(d,J=9.5Hz,1H),8.01-7.99(m,2H),7.47-7.45(m,1 H),4.95-4.92(m,1H),4.67-4.62(m,2H),4.61-4.22(m,4H),4.07-3.7 5(m,1H),3.51-3.49(m,2H),3.16-2.82(m,2H),2.08(d,J=15.3Hz,3H).

[0216] Example 50: Synthesis of methyl (R)-4-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)piperazine-2-carboxylate

[0217] [ka] To a solution of intermediate B (100 mg, 0.29 mmol) in NMP (2 mL) was added 1-tert-butyl 2-methyl (2R)-piperazine-1,2-dicarboxylate (107.86 mg, 0.44 mmol), TEA (0.12 mL, 0.88 mmol). The sealed vial was irradiated in a microwave reactor at 140 °C for 2.5 h. The reaction was purified using silica gel column chromatography eluting with water / CH3CN / HCOOH to give 1-(tert-butyl) 2-methyl (R)-4-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)piperazine-1,2-dicarboxylate (60 mg, 0.11 mmol, 37% yield) as a white solid. LCMS: RT=1.871 min, MS m / z(ESI)[M+H] + =548.2.

[0218] A solution of 1-(tert-butyl) 2-methyl (R)-4-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)piperazine-1,2-dicarboxylate (55 mg, 0.10 mmol) in formic acid (2 mL) was stirred at room temperature for 2 h. The reaction was purified by preparative HPLC to give Example 50 (15.66 mg, 0.03 mmol, 35% yield) as a white solid. LCMS: RT=1.309 min, MS m / z (ESI) [M+H] + =448.1. 1 H NMR(400MHz,DMSO-d6)δ9.80(s,1H),8.76(s,1H),8.42(s,1H),8.27(d,J=9.4Hz,1H),8.18(s,1H),8.00(d,J=1.2Hz,2H),7.48(d,J=9.5Hz,1H),4. 63(d,J=6.4Hz,2H),4.37-4.34(m,1H),3.95-3.93(m,1H),3.66(s,3H),3. 61-3.54(m,2H),3.49-3.46(m,2H),3.03-3.01(m,1H),2.75-2.71(m,1H).

[0219] Example 51: Synthesis of (R)-4-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)piperazine-2-carboxylic acid

[0220] [ka] To a solution of intermediate B (100 mg, 0.29 mmol) in NMP (2 mL) was added 1-tert-butyl 2-methyl (2R)-piperazine-1,2-dicarboxylate (107.86 mg, 0.44 mmol), TEA (0.123 mL, 0.88 mmol). The sealed vial was irradiated in a microwave reactor at 140° C. for 2.5 h. The reaction was purified using silica gel column chromatography eluting with water / CH3CN / HCOOH to give (R)-1-(tert-butoxycarbonyl)-4-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)piperazine-2-carboxylic acid (50 mg, 0.09 mmol, 32% yield) as a white solid. LCMS: RT=1.094 min, MS m / z(ESI)[M+H] + =534.1.

[0221] To a solution of (R)-1-(tert-butoxycarbonyl)-4-(6-(((6-cyanopyridin-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)piperazine-2-carboxylic acid (45 mg, 0.08 mmol) in formic acid (2 mL) the reaction was stirred at room temperature for 2 h. The reaction was purified by preparative HPLC to give Example 51 (11.18 mg, 0.03 mmol, 31% yield) as a white solid. LCMS: RT=1.249 min, MS m / z (ESI) [M+H] + =434.2. 1H NMR(400MHz,DMSO-d6)δ13.35(s,1H),9.83(s,1H),8.76(s,1H),8.47(s,1H),8.32(d,J=9.3Hz,1H),8.01(s ,2H),7.51(d,J=9.3Hz,1H),4.75-4.73(m,1H),4.63(d,J=6.1Hz,2H),4.37-4.34(m,1H),3.44-2.99(m,6H).

[0222] Example 60: Synthesis of (R)-N-(2-chloro-4-cyanobenzyl)-5-hydroxy-2-(3-(hydroxymethyl)piperazin-1-yl)-1,7-naphthyridine-6-carboxamide

[0223] [ka] To a solution of 2-chloro-N-(2-chloro-4-cyanobenzyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide (250 mg, 0.67 mmol) in DMSO (5 mL), TEA (0.279 mL, 2.01 mmol), tert-butyl (R)-2-(hydroxymethyl)piperazine-1-carboxylate (23 mg, 0.20 mmol) were added and the reaction was stirred at 100 °C under N2 for 2 h. The reaction was diluted with water (200 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were separated and further washed with saturated NaCl solution (100 mL × 3) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with methanol (0-15%) in chloroform. The organic layer was collected, concentrated in vacuo, and dried to give the title compound tert-butyl (R)-4-(6-((2-chloro-4-cyanobenzyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (50 mg, 0.12 mmol, 50% yield) as a white solid. LCMS: RT=1.471 min, MS m / z (ESI) [M+H] + =553.3.

[0224] To a solution of (R)-4-(6-((2-chloro-4-cyanobenzyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (270 mg, 0.49 mmol) was added TFA (2 mL, 26.93 mmol) and the reaction was stirred at room temperature for 1 h. The reaction mixture was poured into saturated Na2CO3 (100 mL), extracted with EtOAc (40 mL x 3), the organic layer was dried over Na2SO4, filtered and evaporated to give Example 60 (200 mg, 0.44 mmol, 90% yield) as a yellow oil. LCMS: RT = 0.740 min, MS m / z (ESI) [M+H] + =453.0. 1 H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.82(s,1H),8.52(d,J=8.2Hz,1H),8.34(s,1H),8.14(s,1H),7.87(d,J=8.0Hz,1H) ),7.57(d,J=8.0Hz,2H),5.08-5.06(m,1H),4.66-4.52(m,4H),3.59-3.51(m,2H),3.21-3.18(m,2H),2.98-2.88(m,4H).

[0225] Example 59: Synthesis of (R)-N-(2-chloro-4-cyanobenzyl)-5-hydroxy-2-(3-(hydroxymethyl)-4-methylpiperazin-1-yl)-1,7-naphthyridine-6-carboxamide

[0226] [ka] To a solution of (R)-N-(2-chloro-4-cyanobenzyl)-5-hydroxy-2-(3-(hydroxymethyl)piperazin-1-yl)-1,7-naphthyridine-6-carboxamide (50 mg, 0.11 mmol) in DCM (1 mL) was added sodium bis(acetyloxy)boranyl acetate (69.86 mg, 0.33 mmol), formaldehyde (18.42 mg, 0.22 mmol) and the reaction was stirred at room temperature for 1 h. The reaction was diluted with EtOAc (30 mL) and water (50 mL). The organic layer was separated and concentrated in vacuo. The residue was purified using preparative HPLC to give Example 59 (13.39 mg, 0.03 mmol, 26% yield) as a pale yellow solid. LCMS: RT=1.376 min, MS m / z (ESI) [M+H] + =467.2. 1 H NMR(400MHz,DMSO-d6)δ9.73(s,1H),8.42(s,1H),8.28(d,J=9.4Hz,1H),8.21(s,1H),8.07( d,J=1.5Hz,1H),7.81(dd,J=8.0,1.4Hz,1H),7.52(d,J=8.1Hz,1H),7.46(d,J=9.4Hz,1H),4. 64(d,J=6.1Hz,2H),4.55-4.44(m,1H),4.37-4.35(m,1H),3.72-3.70(m,2H),3.42-3.40(m,1 H),3.21-3.13(m,1H),2.98-2.83(m,2H),2.28(s,3H),2.24-2.20(m,1H),2.11-2.04(m,1H).

[0227] Example 63: Synthesis of (R)-2-(4-acetyl-3-(hydroxymethyl)piperazin-1-yl)-N-(2-chloro-4-cyanobenzyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide

[0228] [ka] To a solution of (R)-N-(2-chloro-4-cyanobenzyl)-5-hydroxy-2-(3-(hydroxymethyl)piperazin-1-yl)-1,7-naphthyridine-6-carboxamide (70 mg, 0.15 mmol) in DCM (3 mL) was added acetyl chloride (0.105 mL, 0.10 mmol) and the reaction was stirred at room temperature for 1 h. The reaction was diluted with EtOAc (30 mL) and water (50 mL). The organic layer was separated and concentrated in vacuo. The residue was purified using preparative HPLC to give Example 63 (6.75 mg, 0.01 mmol, 9% yield) as a pale yellow solid. LCMS: RT=1.620 min, MS m / z (ESI) [M+H] + =495.2. 1 H NMR(400MHz,DMSO-d6)δ9.77(s,1H),8.40-8.38(m,1H),8.30(d,J=8.9Hz,1H),8.26(s, 1H),8.08(s,1H),7.81(d,J=8.3Hz,1H),7.52(d,J=8.0Hz,1H),7.46-7.44(m,1H),4.86 -4.84(m,1H),4.65-4.63(m,2H),4.55-4.47(m,2H),4.35-4.33(m,2H),4.07-4.05(m,1 H),3.30-3.78(m,1H),3.50(d,J=7.1Hz,2H),3.00-2.96(m,1H),2.09(d,J=14.9Hz,3H).

[0229] Example 72: Synthesis of N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(4-(3-hydroxypropanoyl)piperazin-1-yl)-1,7-naphthyridine-6-carboxamide

[0230] [ka] To a solution of N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(piperazin-1-yl)-1,7-naphthyridine-6-carboxamide (50 mg, 0.13 mmol) in DCM (4 mL) was added 3-hydroxypropanoic acid (0.011 mL, 0.13 mmol), HATU (73.23 mg, 0.19 mmol), and DIEA (0.064 mL, 0.39 mmol) and the reaction was stirred at room temperature for 16 h. The reaction mixture was poured into saturated NaCl (100 mL) and extracted with ethyl acetate (40 mL×3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give Example 72 (7.07 mg, 0.02 mmol, 12% yield) as a pale yellow solid. LCMS: RT=1.420 min, MS m / z(ESI)[M+H] + =462.1. 1 H NMR(400MHz,DMSO-d6)δ13.37(s,1H),9.77(t,J=6.1Hz,1H),8.76(s,1H),8.45(s,1H),8.29(d,J=9.4Hz,1H),8.00(s,2H),7 .50(d,J=9.5Hz,1H),4.63(d,J=6.2Hz,2H),4.55(d,J=5.3Hz,1H),3.84-3.81(m,4H),3.69-3.66(m,6H),2.57-2.55(m,2H).

[0231] Example 73: Synthesis of N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(4-(3-methoxypropanoyl)piperazin-1-yl)-1,7-naphthyridine-6-carboxamide

[0232] [ka] To a solution of N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(piperazin-1-yl)-1,7-naphthyridine-6-carboxamide (50 mg, 0.13 mmol) in DCM (4 mL) was added 3-hydroxypropanoic acid (0.011 mL, 0.13 mmol), HATU (73.23 mg, 0.19 mmol), and DIEA (0.064 mL, 0.39 mmol) and the reaction was stirred at room temperature for 16 h. The reaction mixture was poured into saturated NaCl (100 mL) and extracted with ethyl acetate (40 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified using preparative HPLC to give Example 73 (6.18 mg, 0.01 mmol, 6% yield) as a white solid. LCMS: RT=1.505 min, MS m / z(ESI)[M+H] + =476.2. 1 H NMR(400MHz,DMSO-d6)δ13.37(s,1H),9.77(t,J=6.3Hz,1H),8.76(s,1H),8.45(s,1H),8.29(d,J=9.4Hz,1H),8.00(d,J=1.2H) z,2H),7.50(d,J=9.5Hz,1H),4.63(d,J=6.3Hz,2H),3.83-3.81(m,4H),3.65-3.56(m,6H),3.24(s,3H),2.64(t,J=6.6Hz,2H).

[0233] Example 85: Conjugation of N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(2-oxomorpholino)-1,7-naphthyridine-6-carboxamide

[0234] [ka] To a solution of Intermediate B (150 mg, 0.44 mmol) in DMSO (5 mL) was added ethyl (2-hydroxyethyl)glycinate (195 mg, 1.32 mmol) and TEA (222 mg, 2.2 mmol) and the reaction was stirred for 16 h at 100° C. The mixture was concentrated and purified by preparative TLC to give Example 85 (19.20 mg, 11%).

[0235] Example 85: LCMS: 405.1 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ13.41(s,1H),9.79(s,1H),8.76(s,1H),8.52(s,1H),8.36(d,J=9.3 Hz,1H),8.00(d,J=1.4Hz,2H),7.39(d,J=9.4Hz,1H),4.70-4.54(m,6H),4.00-3.88(m,2H).

[0236] Example 124: Synthesis of 2-(4-aminopiperidin-1-yl)-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide

[0237] [ka] To a solution of Example 123 (100 mg, 0.198 mmol) was added formic acid (3 mL, 0.225 mmol) and the reaction was stirred at 25° C. for 3 h. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC to give Example 124 (34.39 mg, 43%). LCMS: 404.3 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.76(s,1H),8.38(s,1H),8.35(s,1H),8.25(s,1H),8.01-7.97(m,2H),7.47(d,J=9.5Hz,1H), 4.63(d,J=5.4Hz,2H),4.57(d,J=13.5Hz,2H),3.25-3.17(m,1H),3.10(t,J=11.9Hz,2H),1.96(d,J=12.5Hz,2H),1.45-1.42(m,2H).

[0238] Example 126: Synthesis of (S)-2-(3-aminopyrrolidin-1-yl)-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide

[0239] [ka] To a solution of Example 125 (110 mg, 0.225 mmol) was added formic acid (3 mL, 0.225 mmol) and the reaction was stirred at 25° C. for 3 h. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC to give Example 126 (22.01 mg, 24%). LCMS: 390.5 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.76(s,1H),8.37(d,J=18.9Hz,2H),8.25(d,J=9.2Hz,1H),8.00(s,2H),7.08( d,J=9.1Hz,1H),4.64(d,J=4.8Hz,2H),3.81-3.69(m,4H),3.65-3.62(m,1H),2.23-2.21(m,1H),1.99-1.97(m,1H).

[0240] Example 15: Synthesis of (6-cyanopyridin-3-yl)methyl (R)-5-hydroxy-2-(3-hydroxypyrrolidin-1-yl)-1,7-naphthyridine-6-carboxylate

[0241] [ka] To a solution of 5-(bromomethyl)picolinonitrile (100 mg, 0.51 mmol) in DMF (3 mL) was added the carboxylic acid (155.23 mg, 0.56 mmol, obtained by a procedure similar to that of Example 3), NaHCO3 (94.74 mg, 1.13 mmol) and the reaction was stirred at room temperature for 16 h. The reaction was diluted with H2O (30 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with aqueous NaCl (30 mL x 3), dried and concentrated in vacuo. The residue was purified by preparative HPL to give Example 15 (4.1 mg, 2%). LCMS: 392.0 [M+H] + , 1H NMR(400MHz,DMSO-d6)δ8.90(s,1H),8.32-8.08(m,5H),7.14-6.91(m,1H),5.52-5.5 0(m,2H),5.03-5.01(m,1H),4.45-4.43(m,1H),3.63-3.61(m,4H),2.03-2.01(m,3H).

[0242] Example 102: Synthesis of N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-2-(2-oxopiperazin-1-yl)-1,7-naphthyridine-6-carboxamide

[0243] [ka] A solution of Example 101 (150 mg, 0.298 mmol) in HCl / EA (3M, 2 mL) was stirred at room temperature for 1 h. The mixture was filtered and concentrated. The crude product was purified by preparative HPLC to give Example 102 (24.15 mg, 19%). LCMS: 404.2 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ13.61(s,1H),10.00(s,1H),9.65(s,2H),8.80(d,J=15.4Hz,2H),8.70(d,J=9.3Hz,1H),8.3 6(d,J=9.2Hz,1H),8.02(d,J=1.4Hz,2H),4.68(d,J=6.2Hz,2H),4.43-4.23(m,2H),4.05(s,2H),3.67-3.50(m,2H).

[0244] Example 128: 2-(3-aminoazetidin-1-yl)-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide

[0245] [ka] A mixture of Example 127 (28 mg, 0.059 mmol) in HCl / EA (3M, 5 mL) was stirred at room temperature for 1 h, and the reaction was concentrated in vacuo. The residue was purified by preparative HPLC to give Example 128 (29.91 mg, 38%). LCMS: 376 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ9.77(s,1H),8.76(s,1H),8.41(s,1H),8.23(d,J=9.0Hz,1H),8.00(s,2H),6.9 2(d,J=9.1Hz,1H),4.63(d,J=6.4Hz,2H),4.33(t,J=8.1Hz,2H),3.93-3.85(m,1H),3.82-3.73(m,2H).

[0246] Example 134: Synthesis of tert-butyl 4-(6-(((5-cyanopyrazin-2-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)piperazine-1-carboxylate

[0247] [ka] To a solution of tert-butyl 4-(6-(((5-chloropyrazin-2-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridin-2-yl)piperazine-1-carboxylate (150 mg, 0.300 mmol, obtained in general procedure D) in DMF (2 mL) was added Zn(CN) (35.23 mg, 0.300 mmol), Pd(dppf)Cl (43.91 mg, 0.060 mmol) and the reaction was stirred under N at 130° C. for 16 h. The reaction was poured into water (50 mL) and extracted with EA (30 mL×3). The organic layer was washed with aqueous NaCl (30 mL×3), dried over NaSO and concentrated. The crude product was purified by preparative HPLC to give Example 134 (8.28 mg, 5%). LCMS: 491.2 [M+H] + , 1H NMR(400MHz,DMSO-d6)δ13.29(s,1H),9.66-9.65(m,1H),9.18(d,J=1.2Hz,1H),8.88(s,1H),8.46(s,1H),8.30( d,J=9.4Hz,1H),7.49(d,J=9.4Hz,1H),4.81(d,J=6.0Hz,2H),3.83-3.81(m,4H),3.49-3.46(m,4H),1.44(s,9H).

[0248] Example 163: Synthesis of N-((6-cyanopyridin-3-yl)methyl)-5-methoxy-2-morpholino-1,7-naphthyridine-6-carboxamide

[0249] [ka] To a solution of Example 10 (100 mg, 0.256 mmol) in acetone (2 mL) was added MeI (360 mg, 2.536 mmol) and K2CO3 (180 mg, 1.302 mmol), the reaction was heated to 50° C. for 2 h, the solution was diluted with water (10 mL) and extracted with EA (5 mL×3), the EA layers were combined, washed with brine (5 mL), dried over Na2SO4, concentrated and the residue was purified by preparative HPLC to give Example 163 (3.76 mg, 4%). LCMS: 405 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ11.84(s,1H),8.76(s,1H),8.35(d,J=9.4Hz,1H),8.13(s,1H),8 .01(s,2H),7.42(d,J=9.3Hz,1H),4.64(d,J=5.9Hz,2H),4.47(s,3H),3.75-3.72(m,8H).

[0250] Example 40: Synthesis of 5-hydroxy-N-((6-hydroxypyridin-3-yl)methyl)-2-morpholino-1,7-naphthyridine-6-carboxamide

[0251] [ka] To a solution of Example 34 (129 mg, 0.33 mmol) in acetonitrile (5.0 mL) was added iodotrimethylsilane (0.14 mL, 1.00 mmol). The resulting mixture was stirred at 80° C. for 18 hours. The residue was purified by preparative HPLC to give Example 40 (50.95 mg, 41%). LCMS: 382.0 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ13.60(s,1H),11.48(s,1H),9.47(t,J=6.1Hz,1H),8.41(s,1H),8.28(d,J=9.4Hz,1H),7.51(dd,J=9.5, 2.6Hz,1H),7.48(d,J=9.5Hz,1H),7.33(d,J=2.1Hz,1H),6.32(d,J=9.4Hz,1H),4.24(d,J=6.3Hz,2H),3.75(s,4H),3.73(s,4H).

[0252] The following compounds were made according to the general procedures set out in Table 2 below.

[0253] [Table 2-1]

[0254] [Table 2-2]

[0255] [Table 2-3]

[0256] Biological Examples Example A: PHD2 Enzyme Assay Procedure Compound DMSO stock preparation: All compounds were reconstituted with DMSO to a 20 mM stock.

[0257] Compound storage: All compounds in DMSO were stored at room temperature in a desiccator for short term storage (up to 3 months). Leftover compounds were stored at -20°C for long term storage.

[0258] Preparation of working stock: Reference Roxadustat (FG-4592) was serially diluted 3-fold in DMSO over 10 doses starting at 400 μM. Compounds were serially diluted 3-fold in DMSO over 10 doses starting at 400 μM. · A 200x positive control (400μM, FG-4592) and a 200x solvent control (100% DMSO) were prepared. · The compound plate was centrifuged at 1000 rpm for 1 minute.

[0259] Compound screening: · a) 40nl of compound dilutions were transferred to each well of the assay plate using the Echo 655. · b) Seal the assay plate and centrifuge the compound plate at 1000 rpm for 1 minute. c) Prepare 4 μL of 2xPHD2 enzyme working solution and add to individual wells of the assay plate. d) Seal the assay plate and centrifuge the compound plate at 1000 rpm for 1 minute. Incubate the plate at room temperature for 30 minutes. e) Prepare 4 μL of 2xPHD2 substrate working solution and add to each well of the assay plate. f) 4 μL of 4x stop solution was prepared and added to each well of the assay plate. g) A 4x detection solution was prepared with AlphaScreen Streptavidin Donor beads, AlphaScreen Protein A Acceptor beads, and Hydroxy-HIF-1α (Pro564) (D43B5) XP® Rabbit mAb. h) 4 μL of 4x Detection Solution was added to each well of the assay plate. Step d was repeated. i) Read the Alphascreen signal on an Envision HTS plate reader.

[0260] Data analysis The ALPHASCREEN signal (ALPcmpd) is calculated for each well. 2.2 % Inhibition is calculated as follows:

[0261]

number

[0262]

number

[0263]

number

[0264] Example C: Assay of Caco-2 HIF1α-HiBiT Cells: Caco2-HIF1α-HiBiT-clone-1 cells.

[0265] Culture medium: EMEM contains 20% FBS and 1% penicillin-streptomycin for Caco-2.

[0266] Cell passaging procedure Clean the work surface of the biosafety cabinet with 75% ethanol and let sit for approximately 5 minutes before using the cabinet. Aspirate the cell medium and gently rinse the cell layer twice with 5 mL of DPBS. Then, remove the DPBS. Add 2 ml of 0.25% trypsin to the flask and place in a 37°C, 5% CO2 incubator for 2 minutes. After 2 min of trypsinization, trypsin was quenched with 10 ml of cell culture medium. The cells were gently pipetted up and down to dissociate any cell clumps, and the cell suspension was transferred to a 15 ml tube. Cell density was confirmed using a cell counter. · Dilute the cell suspension with medium and transfer 2.0*106 cells into a T75 flask. The cells were maintained in a humidified incubator at 37°C and 5% CO2 for 3 days.

[0267] Plating cells (Day 1) -Plating medium was prepared. · Aspirate the cell culture medium. Wash the cells gently with 10 mL of PBS and remove the PBS. Dissociate the cells with 3 mL of 0.25% trypsin and terminate the digestion with 10 mL of cell culture medium. Cell density was measured using a cell counter. Caco-2-HIF1α-HiBiT-Clone-1 cells were plated in 384-well plates (Corning-3765) at a density of 5.5k cells per well in 20 μl of medium. Keep the cells in the incubator overnight.

[0268] Compound treatment (day 3) Compound stock solutions were dissolved in DMSO and working concentrations were achieved by serial dilution in cell culture medium. Final compound concentrations were achieved by adding 20 μL of medium per well containing different compounds at the desired concentrations. · The cells were incubated in a 37℃, 5% CO2 incubator for 6 hours.

[0269] Detection (Day 3) · Prepare 2x Detection Solution: Dilute LgBiT Protein, and Nano-Glo® HiBiT Lytic Substrate 1:2:100 into an appropriate amount of room temperature Nano-Glo® HiBiT Lytic Buffer in a new tube. Prepare 1x detection solution: Add an equal volume of PBS to 2x detection solution to prepare 1x detection solution. Wash cells with PBS and add 30ul of 1x solution to wells and mix. Lysates were allowed to equilibrate for at least 10 minutes for LgBiT and HiBiT. Luminescence was measured using Envision.

[0270] The data for Examples A and C are shown in Table 3.

[0271] [Table 3-1]

[0272] [Table 3-2]

[0273] [Table 3-3]

Claims

1. Formula (I) 【Chemical 1】 or a pharmaceutically acceptable salt, or stereoisomer thereof, During the ceremony, R １ optionally independently represent one or more R １ａ is a monocyclic heterocycloalkyl substituted with Each R １ａ are independently halogen, —CN, —NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same atom １ａ together to form an oxo X is N or CR ２ and R ２ is hydrogen, fluoro, chloro, bromo, -CN, -NO ２ , —OH, —OR ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ is heteroalkyl, R ３ is hydrogen, halogen, -CN, -NO ２ , —OH, —OR ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ is heteroalkyl, R ４ is hydrogen, halogen, -CN, -NO ２ , —OH, —OR ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ is heteroalkyl, R ５ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ is heteroalkyl, Y is —O—, —S—, or —NR ６ - and R ６ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ is heteroalkyl, L is -(CR ７ R ８ ) ｐ - and Each R ７ and R ８ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ is heteroalkyl, or R on the same carbon ７ and R ８ together form a cycloalkyl or heterocycloalkyl, each of which optionally has one or more R ７ａ is replaced by Each R ７ａ are independently halogen, —CN, —NO ２ , —OH, —OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ is heteroalkyl, p is 0 to 4; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R ９ are independently halogen, —CN, —NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R ９ａ is replaced by Or, two R on the same atom ９ together to form an oxo Each R ９ａ are independently halogen, —CN, —NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same atom ９ａ together to form an oxo n is 0 to 4; Each R ａ are independently １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Each R ｂ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Each R ｃ and R ｄ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Or, R ｃ and R ｄ together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R, and Each R is independently a halogen, —CN, —OH, —OC １ -C ６ Alkyl, —S(═O)C １ -C ６ Alkyl, —S(═O) ２ C １ -C ６ Alkyl, —S(═O) ２ NH ２ , -S(=O) ２ NHC １ -C ６ Alkyl, —S(═O) ２ N (C １ -C ６ alkyl) ２ , -NH ２ , -NHC １ -C ６ Alkyl, —N(C １ -C ６ alkyl) ２ , -NHC(=O)OC １ -C ６ Alkyl, —C(═O)C １ -C ６ Alkyl, —C(═O)OH, —C(═O)OC １ -C ６ Alkyl, —C(═O)NH ２ , -C(=O)N(C １ -C ６ alkyl) ２ , -C(=O)NHC １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ is heteroalkyl, or A compound, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein two R on the same atom are joined together to form oxo.

2. The compound of claim 1, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein X is CR 2 and R 2 is hydrogen, fluoro, or C 1 -C 6 alkyl.

3. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, and R 4 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

4. The compound of claim 3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is hydrogen and R 4 is hydrogen.

5. The compound of claim 1, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein R 5 is hydrogen or C 1 -C 6 alkyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 is hydrogen.

7. The compound of claim 1, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein Y is —NR 6 — and R 6 is hydrogen or C 1 -C 6 alkyl.

8. The compound of claim 1, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein p is 1 and R 7 and R 8 are independently hydrogen or C 1 -C 6 alkyl.

9. The compound of claim 8, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein each R 7 and R 8 is hydrogen.

10. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is phenyl, or a 5- or 6-membered heteroaryl.

11. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is a 6-membered heteroaryl.

12. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1 or 2, and each R 9 is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

13. The compound of claim 1, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein n is 1 and R 9 is halogen or —CN.

14. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is a 5- to 7-membered monocyclic heterocycloalkyl optionally and independently substituted with one or two R 1a , and the monocyclic heterocycloalkyl contains 1 to 3 ring nitrogen atoms.

15. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 1a is independently halogen, -OH, -OR a , -NR b C(=O)R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, or cycloalkyl, or two R 1a on the same atom together form oxo.

16. The compound of claim 15, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein each R 1a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or —C(═O)OR b .

17. The following 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 10. The compound of claim 1, or a pharmaceutically acceptable salt, or stereoisomer thereof, selected from the group consisting of:

18. The compound 【Chemistry 16】 2. The compound of claim 1, wherein:

19. A pharmaceutical composition comprising a therapeutically effective amount of a compound described in any one of claims 1 to 18, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

20. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for treating inflammatory bowel disease (IBD).

21. Use of the pharmaceutical composition of claim 19 in the manufacture of a medicament for treating inflammatory bowel disease (IBD).