Tyk2 inhibitors and uses thereof

Abstract

Described herein are compounds of Formula (I) that are useful in the treatment of TYK2-mediated diseases. In some embodiments, the TYK2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a disease associated with transplantation.

Description

[0001] Related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 079,217, filed September 16, 2020, the contents of which are incorporated herein by reference in their entirety.

[0003] Application Areas

[0004] This article describes compounds, methods for preparing such compounds, pharmaceutical compositions and medicines containing such compounds, and methods for using such compounds to inhibit non-receptor tyrosine protein kinase 2 (“TYK2”) (also known as tyrosine kinase 2). Background Technology

[0005] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. The mammalian JAK family consists of four members: TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are essential components of cytokine signal transduction. TYK2 is associated with the cytoplasmic domains of type I and type II cytokine receptors, as well as interferon type I and type III receptors, and is activated by these receptors upon cytokine binding. Cytokines associated with TYK2 activation include interferons (such as IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as restriction factors)) and interleukins (such as IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, L-22, IL-23, IL-27, IL-31, oncosin M, ciliary neurotrophic factor, myocardial trophic factor 1, myocardial trophic factor-like cytokines, and LIF). Activated TYK2 then continues to phosphorylate further signal transduction proteins, such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

[0006] TYK2, activated by IL-23, is associated with inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. A genome-wide association study of 2,622 psoriasis patients identified an association between disease susceptibility and TYK2. Knockout of TYK2 or inhibition of tyrphostin significantly reduced IL-23 and IL-22-induced dermatitis.

[0007] TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell proliferation (GCH) and excessive mucus secretion are mediated by IL-13-induced TYK2 activation, which in turn activates STAT6.

[0008] TYK2 activity reduction protects joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis. Mechanistically, TYK2 activity reduction reduces the production of Thl / Thl7-associated cytokines and matrix metalloproteinases and other key inflammatory markers.

[0009] TYK2 knockout mice are completely resistant to experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)) with no CD4 T cell infiltration in the spinal cord compared to controls, indicating that TYK2 is critical for the pathogenic CD4-mediated disease progression in MS. This confirms earlier studies linking increased TYK2 expression to MS susceptibility. Loss-of-function mutations in TYK2 lead to reduced demyelination of neurons and increased remyelination, further indicating the role of TYK2 inhibitors in treating MS and other CNS demyelinating diseases.

[0010] TYK2 is the only signal transduction messenger shared by IL-12 and IL-23. TYK2 knockout reduces methylated BSA injection-induced footpad thickness, imiquimod-induced psoriasis-like skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice.

[0011] Various linkage and association studies of type I IFN signaling genes with systemic lupus erythematosus (SLE, an autoimmune disease) show a strong and significant correlation between loss-of-function mutations in TYK2 and reduced SLE prevalence in affected family members. Genome-wide association studies of individuals with SLE versus unaffected cohorts show a highly significant correlation between the TYK2 locus and SLE.

[0012] TYK2 has been shown to play an important role in maintaining tumor surveillance, with TYK2 knockout mice showing impaired cytotoxic T cell responses and accelerated tumor development. However, these effects are associated with effective suppression of natural killer (NK) and cytotoxic T lymphocytes, indicating that TYK2 inhibitors are well suited for treating autoimmune diseases or transplant rejection. Although other JAK family members such as JAK3 have similar roles in the immune system, TYK2 is considered a better target because it is involved in fewer but more closely related signal transduction pathways, resulting in fewer off-target effects.

[0013] Studies on T-cell acute lymphoblastic leukemia (T-ALL) have shown that T-ALL is highly dependent on IL-10 through TYK2, maintains cancer cell survival through STAT1 -mediated signaling, and upregulation of the anti-apoptotic protein BCL2. Knockdown of TYK2 (but not other JAK family members) reduced cell growth. TYK2-specific activating mutations that promote cancer cell survival include mutations in the FERM domain (G36D, S47N, and R425H), the JH2 domain (V73II), and the kinase domain (E957D and R1027H). However, the kinase function of TYK2 was also found to be required for increased cancer cell survival, as TYK2 enzymes with kinase-dead mutations (M978Y or M978F) in addition to an activating mutation (E957D) that leads to transformation failure.

[0014] Accordingly, it is proposed that selective inhibition of TYK2 is a suitable target for patients with tumors that overexpress IL-10 and / or BCL2, such as 70% of adult T-cell leukemia cases. TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid-beta (Ab) peptides. TYK2 phosphorylation of STAT3 is reduced upon Ab administration, leading to a reduction in neuronal cell death and an increase in STAT3 phosphorylation observed in post-mortem brains of Alzheimer’s patients.

[0015] Inhibition of the JAK-STAT signaling pathway has also been linked to hair growth, and reversal of hair loss associated with alopecia areata.

[0016] Accordingly, compounds that inhibit TYK2 activity are beneficial, particularly those that are selective for JAK2. Such compounds should produce pharmacological responses that are beneficial for treating one or more of the conditions described herein without the side effects associated with inhibiting JAK2.

[0017] Accordingly, there is a need to provide new inhibitors with more effective or more favorable pharmaceutically relevant properties, such as selectivity over other JAK kinases, particularly JAK2. SUMMARY

[0019] Described herein are compounds useful for treating TYK2-mediated diseases. In some embodiments, the TYK2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a disease associated with transplantation. In some embodiments, the TYK2-mediated disease is a cancer.

[0020] Disclosed herein are compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0021]

[0022] wherein:

[0023] L is C1-C4 alkylene; wherein one or two carbon atoms are optionally replaced by a heteroatom selected from oxygen, sulfur, nitrogen, or phosphorus; wherein L is optionally substituted with one or more R L ;

[0024] each R L is independently deuterium, halogen, -CN, -OR b , -NO2, -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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R L on the same carbon form an oxo, cycloalkyl, or heterocycloalkyl group; ring A is heteroaryl, and ring B is cycloalkyl or heterocycloalkyl;

[0025] or ring A is aryl or heteroaryl, and ring B is heterocycloalkyl or 5- to 8-membered cycloalkyl; each R A is independently deuterium, halogen, -CN, -OR b , -SR b , -S(=O)R a , -S(=O)2R a , -NO2, -NR c R d , -NHS(=O)2R a , -S(=O)2NR c R d , -C(=O)R a , -OC(=O)R a , -C(=O)OR b , -OC(=O)OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR bC1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R A1 substituents;

[0026] each R A1 is independently deuterium, halogen, -CN, -OR b , -SR b , -S(=O)R a , -S(=O)2R a , -NO2, -NR c R d , -NHS(=O)2R a , -S(=O)2NR c R d , -C(=O)R a , -OC(=O)R a , -C(=O)OR b , -OC(=O)OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0027] or two R A1 on the same carbon are taken together to form an oxo;

[0028] n is 0-4;

[0029] each R B is independently deuterium, halogen, -CN, -OR b , -SR b , -S(=O)R a , -S(=O)2R a , -NO2, -NR c R d , -NHS(=O)2Ra -S(=O)2NR c R d -C(=O)R a -OC(=O)R a -C(=O)OR b -OC(=O)OR b -C(=O)NR c R d -OC(=O)NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R B1 ;

[0030] or two R B on the same carbon are taken together to form an oxo;

[0031] each R B1 is independently deuterium, halogen, -CN, -OR b , -SR b , -S(=O)R a , -S(=O)2R a , -NO2, -NR c R d , -NHS(=O)2R a , -S(=O)2NR c R d , -C(=O)R a , -OC(=O)R a , -C(=O)OR b , -OC(=O)OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a, -NR b C(=O)OR b , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C 1- C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0032] or two R B1 on the same carbon form an oxo;

[0033] m is 0-4;

[0034] is a single or double bond;

[0035] X 1 is N and X 2 is -C=, or X 2 is -N and X 1 is -C=;

[0036] Y 3 is CR 3 or N;

[0037] Y 6 is CR 6 or N;

[0038] Y 8 is CR 8 or N;

[0039] Y 9 is CR 9 or N;

[0040] R 3 , R 6 , R 8 and R 9 are independently hydrogen, deuterium, halogen, -CN, -OR b , -SR b , -S(=O)R a , -S(=O)2R a , -NO 2 , -NR c R d , -NHS(=O)2R a , -S(=O)2NR c R d , -C(=O)R a , -OC(=O)R a , -C(=O)OR b , -OC(=O)OR b , -C(=O)NR c Rd -OC(=O)NR c R d -OC(=O)R b -OC(=O)OR c -OC(=O)NR d R b -OC(=O)R a -OC(=O)OR b -OC(=O)NR b C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, or C2-C6alkynyl;

[0041] R 4 is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 4a ;

[0042] each R 4a is independently deuterium, halogen, -CN, -OR b , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0043] or two R 4a on the same carbon are taken together to form an oxo;

[0044] R 5 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl;

[0045] W is -O-, -S-, or -NR 7 -;

[0046] R 7 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl;

[0047] each R aindependently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6 alkyl, or C1-C6 haloalkyl;

[0048] each R b independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6 alkyl, or C1-C6 haloalkyl; and

[0049] each R c and R d independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6 alkyl, or C1-C6 haloalkyl;

[0050] or R c and R d together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6 alkyl, or C1-C6 haloalkyl.

[0051] Also disclosed herein are pharmaceutical compositions comprising a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a pharmaceutically acceptable excipient.

[0052] Also disclosed herein are methods of inhibiting a TYK2 enzyme in a patient or a biological sample, comprising contacting the patient or the biological sample with a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0053] Also disclosed herein is a method of treating a TYK2-mediated disease, comprising administering to a patient in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments, the TYK2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a disease associated with transplantation. In some embodiments, the disease is associated with Type I interferon, IL-10, IL-12, or IL-23 signaling.

[0054] incorporated by reference

[0055] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purpose identified herein. DETAILED DESCRIPTION

[0057] DEFINITIONS

[0058] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a reagent” includes a plurality of such reagents, and reference to “a cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight or chemical formula, all combinations and subcombinations of ranges, and specific embodiments therein are intended to be included. When referring to a numerical or a numerical range, the term “about” means that the numerical or the numerical range referred to is an approximation within an experimental variability (or statistical experimental error), and therefore in some cases the numerical or the numerical range will vary between 1% and 15% of the stated amount or value. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude other certain embodiments of the present application, e.g., any combination of the described material, ingredients, methods, or processes to the extent that such embodiments are not already expressly described. It is further noted that the claims can be drafted to exclude any

[0059] As used in the specification and the appended claims, the following terms have the meanings indicated below, unless specified otherwise.

[0060] “Oxy” means =0.

[0061] "Alkyl" refers to optionally substituted straight-chain or optionally substituted branched-chain saturated hydrocarbon groups having from one to about ten carbon atoms, or one to six carbon atoms. Examples include, but are not limited to: methyl, ethyl, n-propyl, i-propyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3-methyl-l -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3-methyl-l -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l -butyl, 2-ethyl-l -butyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, t-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, and the like. Whenever a numerical range such as "C1-C6 alkyl" appears herein, it 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 the definition of alkyl also encompasses the term "alkyl" appearing without a numerical range. In some embodiments, alkyl is C1-C6 alkyl. 10 Alkyl, C1-C9 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, or C1 alkyl. Unless otherwise specifically indicated in the specification, alkyl is optionally substituted, for example, with oxo, halo, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkyl is optionally substituted with oxo, halo, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkyl is optionally substituted with oxo, halo, -CN, -CF3, -OH, or -OMe. In some embodiments, alkyl is optionally substituted with halo.

[0062] "Alkenyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monovalent radical having one or more carbon-carbon double bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. The radical can be in the cis- or trans- configuration with respect to the double bonds, and it is 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-buten- dienyl, and the like. Whenever a numerical range such as "C2-C6 alkenyl" appears herein, it 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 the definition of alkenyl also encompasses the term "alkenyl" appearing without a numerical range. In some embodiments, alkenyl is C2-C6 alkenyl. 10 Alkenyl, C2-C9 alkenyl, C2-C8 alkenyl, C 2-C7alkenyl, C2-C6alkenyl, C2-C5alkenyl, C2-C4alkenyl, C2-C3alkenyl, or C2alkenyl. Unless otherwise specified, alkenyl groups are optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkenyl groups are optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkenyl groups are optionally substituted by oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkenyl groups are optionally substituted by halogen.

[0063] “Alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched hydrocarbon monradical having one or more carbon-carbon triple bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3- butadiynyl, and the like. Whenever it appears herein, a numerical range such as “C2-C6alkynyl” indicates that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the term “alkynyl” is also intended to cover instances where the number of carbon atoms is not specified. In some embodiments, alkynyl is C2-C9alkynyl, C2-C8alkynyl, C2-C7alkynyl, C2-C6alkynyl, C2-C5alkynyl, C2-C4alkynyl, C2-C3alkynyl, or C2alkynyl. Unless otherwise specified, alkynyl groups are optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl groups are optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl groups are optionally substituted by oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkynyl groups are optionally substituted by halogen. 10 Alkynyl, C2-C9alkynyl, C2-C8alkynyl, C 2- C7alkynyl, C2-C6alkynyl, C2-C5alkynyl, C2-C4alkynyl, C2-C3alkynyl, or C2alkynyl. Unless otherwise specified, alkynyl groups are optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl groups are optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl groups are optionally substituted by oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkynyl groups are optionally substituted by halogen.

[0064] “Alkylene” refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise specified, alkylene groups can be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkylene groups are optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene groups are optionally substituted by oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkylene groups are optionally substituted by halogen.

[0065] "Alkoxy" refers to a group of the formula -Oalkyl, wherein alkyl is as defined above. Unless otherwise specified, an alkoxy group can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy group is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy group is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, an alkoxy group is optionally substituted with halogen.

[0066] "Aminoalkyl" refers to an alkyl group as defined above substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0067] "Aryl" refers to a group derived from a hydrocarbon ring system containing hydrogen, six to thirty carbon atoms, and at least one aromatic ring. The aryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl group is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl group. Aryl groups include, but are not limited to, groups derived from hydrocarbon ring systems of anthracenylene, naphthalenylene, phenanthrenylene, anthracene, azulene, benzene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pyranthrene, pyrene, and triphenylene. In some embodiments, the aryl group is phenyl. Unless otherwise specified, an aryl group can be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an aryl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, an aryl group is optionally substituted with halogen.

[0068] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which can include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl group is bonded through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyl groups include, but are not limited to, those with three to fifteen carbon atoms (C3-C 15 cycloalkyl), three to ten carbon atoms (C3-C 10"Cycloalkyl" refers to a saturated or partially saturated ring radical of three to eight carbon atoms (C3-C8 cycloalkyl), three to six carbon atoms (C3-C6 cycloalkyl), three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, cycloalkyl is a 3 to 6 membered cycloalkyl. In some embodiments, cycloalkyl is a 5 to 6 membered cycloalkyl. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocyclic groups include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-norbornane, trans-norbornane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptane. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically indicated herein, cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -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.

[0069] "Deuterated alkyl" refers to an alkyl group as defined above that is substituted with one or more deuterium atoms. In some embodiments, the alkyl group is substituted with one deuterium atom. In some embodiments, the alkyl group is substituted with one, two, or three deuterium atoms. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six deuterium atoms. Deuterated alkyl groups include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuterated alkyl group is CD3.

[0070] "Haloalkyl" refers to an alkyl group as defined above that is substituted with one or more halogen atoms. In some embodiments, the alkyl group is substituted with one, two, or three halogen atoms. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six halogens. Haloalkyl groups include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl group is trifluoromethyl.

[0071] "Halo" or "halogen" means bromo, chloro, fluoro, or iodo. In some embodiments, the halo is fluoro or chloro. In some embodiments, the halo is fluoro.

[0072] "Heteroalkyl" refers to an alkyl group in which one or more of the skeletal atoms are selected from an atom other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a Ci-C6heteroalkyl group, wherein the heteroalkyl group comprises 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof, wherein the heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, or -CH(CH3)OCH3. Unless otherwise specified, a heteroalkyl group is optionally substituted, for example, with oxo, halo, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroalkyl group is optionally substituted with oxo, halo, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl group is optionally substituted with oxo, halo, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl group is optionally substituted with halo.

[0073] "Heteroalkyl" refers to an alkyl group in which one or more of the skeletal atoms are selected from an atom other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a Ci-C6heteroalkyl group, wherein the heteroalkyl group comprises 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof, wherein the heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, or -CH(CH3)OCH3. Unless otherwise specified, a heteroalkyl group is optionally substituted, for example, with oxo, halo, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroalkyl group is optionally substituted with oxo, halo, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl group is optionally substituted with oxo, halo, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl group is optionally substituted with halo.

[0074] "Heteroalkyl" refers to an alkyl group in which one or more of the skeletal atoms are selected from an atom other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a Ci-C6heteroalkyl group, wherein the heteroalkyl group comprises 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof, wherein the heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, or -CH(CH3)OCH3. Unless otherwise specified, a heteroalkyl group is optionally substituted, for example, with oxo, halo, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroalkyl group is optionally substituted with oxo, halo, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl group is optionally substituted with oxo, halo, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl group is optionally substituted with halo. 15heterocycloalkyl of two to ten carbon atoms (C2-C10heterocycloalkyl), two to eight carbon atoms (C2-C8heterocycloalkyl), two to six carbon atoms (C2-C6heterocycloalkyl), two to five carbon atoms (C2-C5heterocycloalkyl), or two to four carbon atoms (C2-C4heterocycloalkyl). In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, mercaptomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzo-furan-l-yl, 3-oxo-l,3-dihydroisobenzo-furan-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. It will be appreciated that when referring to the number of carbon atoms in a heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group is different from the total number of atoms (including heteroatoms) that make up the heterocycloalkyl group (i.e., the backbone atoms of the heterocycloalkyl ring). Unless otherwise specifically indicated in the specification, the heterocycloalkyl group is optionally substituted, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl group is optionally substituted with halogen.

[0075] "Heteroaryl" refers to a 5- to 14-membered ring system radical that contains hydrogen atoms, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. Heteroaryl groups can be monocyclic, bicylic, tricyclic, or tetracyclic ring systems, which can include fused rings (heteroaryl is bonded through an aromatic ring atom when fused with a cycloalkyl or heterocycloalkyl ring) or bridged ring systems; the nitrogen, carbon, or sulfur atoms in heteroaryl groups can be optionally oxidized; the nitrogen atoms can be optionally quaternized. In some embodiments, heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, heteroaryl is a 5- to 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxanyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzo dioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopiperonyl, benzopyranyl, benzofuranyl, benzofuranonyl, benzothiophenyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, diphenfuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxazepinyl, oxazolyl, oxiranyl, 1-oxypyridinyl, 1-oxypyrimidinyl, 1-oxypyrazinyl, 1-oxopyridazinyl, 1-phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified, heteroaryl groups are optionally substituted, e.g., with halo, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heteroaryl is optionally substituted with halo, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryl is optionally substituted with halo, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroaryl is optionally substituted with halo.

[0076] As used herein, the terms "treat," "prevent," "ameliorate," and "inhibit," and words stemming therefrom, do not necessarily imply 100%, or complete, treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill will recognize as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of a disease in a mammal. For example, for a disease, including its symptoms or conditions, can be reduced, e.g., by about 100%, by about 90%, by about 80%, by about 70%, by about 60%, by about 50%, by about 40%, by about 30%%, by about 20%, or by about 10%. Further, the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions (e.g., cancer or an inflammatory disease) or symptoms of a disease. Further, for purposes herein, "treatment," "prevention," "amelioration," or "inhibition" include delaying onset of the disease or its symptoms or conditions.

[0077] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a compound disclosed herein being administered to relieve to some extent one or more of the symptoms of the disease or condition (e.g., cancer or an inflammatory disease) being treated. In some embodiments, the result is a decrease and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant decrease in a symptom of a disease. In some embodiments, an appropriate "effective" amount in any individual case is determined using techniques, such as a dose escalation study.

[0078] As used herein, the term "TYK2-mediated" condition, disease, and / or disorder refers to any disease or other deleterious condition in which TYK2 or a mutant thereof is known to play a role. Accordingly, another embodiment relates to treating or lessening one or more diseases in which TYK2 or a mutant thereof is known to play a role. Such TYK2-mediated diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, and diseases associated with transplantation.

[0079] Compounds

[0080] Described herein are compounds that can be used to treat TYK2-mediated diseases. In some embodiments, the TYK2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a disease associated with transplantation. In some embodiments, the TYK2-mediated disease is a cancer.

[0081] Disclosed herein are compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0082]

[0083] wherein:

[0084] L is C1-C4 alkylene; wherein one or two carbon atoms are optionally replaced by a heteroatom selected from oxygen, sulfur, nitrogen, or phosphorus; wherein:

[0085] L is optionally substituted with one or more R L ;

[0086] each R L is independently deuterium, halogen, -CN, -OR b , -NO2, -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 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R L on the same carbon form an oxo, cycloalkyl, or heterocycloalkyl group; ring A is heteroaryl, and ring B is cycloalkyl or heterocycloalkyl;

[0087] or ring A is aryl or heteroaryl, and ring B is heterocycloalkyl or 5- to 8-membered cycloalkyl; each R A is independently deuterium, halogen, -CN, -OR b , -SR b , -S(=O)R a , -S(=O)2R a , -NO2, -NR c R d , -NHS(=O)2R a , -S(=O)2NR c R d , -C(=O)R a , -OC(=O)R a , -C(=O)OR b , -OC(=O)OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -NR b C(=O)NR cR d , -NR b C(=O)R a , -NR b C(=O)OR b , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydro dealkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; A1 ;

[0088] each R A1 is independently deuterium, halogen, -CN, -OR b , -SR b , -S(=O)R a , -S(=O)2R a , -NO2, -NR c R d , -NHS(=O)2R a , -S(=O)2NR c R d , -C(=O)R a , -OC(=O)R a , -C(=O)OR b , -OC(=O)OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydro dealkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0089] or two R A1 on the same carbon are taken together to form an oxo;

[0090] n is 0-4;

[0091] each R B is independently deuterium, halogen, -CN, -OR b , -SR b , -S(=O)Ra -S(=O)2R a -NO2, -NR c R d -NHS(=O)2R a -S(=O)2NR c R d -C(=O)R a -OC(=O)R a -C(=O)OR b -OC(=O)OR b -C(=O)NR c R d -OC(=O)NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R B1 ;

[0092] or two R B on the same carbon are taken together to form an oxo;

[0093] each R B1 is independently deuterium, halogen, -CN, -OR b , -SR b , -S(=O)R a , -S(=O)2R a , -NO2, -NR c R d , -NHS(=O)2R a , -S(=O)2NR c R d , -C(=O)R a , -OC(=O)R a , -C(=O)OR b , -OC(=O)OR b , -C(=O)NR c R d , -OC(=O)NR c R d -NRb C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0094] or two R B1 on the same carbon together form oxo;

[0095] m is 0-4;

[0096] is a single or double bond;

[0097] X 1 is N and X 2 is -C=, or X 2 is -N and X 1 is -C=;

[0098] Y 3 is CR 3 or N;

[0099] Y 6 is CR 6 or N;

[0100] Y 8 is CR 8 or N;

[0101] Y 9 is CR 9 or N;

[0102] R 3 , R 6 , R 8 , R 9 are independently hydrogen, deuterium, halogen, -CN, -OR b , -SR b , -S(=O)R a , -S(=O)2R a , -NO2, -NR c R d , -NHS(=O)2R a , -S(=O)2NR c R d , -C(=O)R a , -OC(=O)R a , -C(=O)ORb -OC(=O)OR b -C(=O)NR c R d -OC(=O)NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b , C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, or C2-C6alkynyl;

[0103] R 4 is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 4a ;

[0104] each R 4a is independently deuterium, halogen, -CN, -OR b , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0105] or two R 4a on the same carbon are taken together to form an oxo;

[0106] R 5 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl;

[0107] W is -O-, -S-, or -NR 7 -;

[0108] R 7 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl;

[0109] each R a independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6 alkyl, or C1-C6 haloalkyl;

[0110] each R b independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6 alkyl, or C1-C6 haloalkyl; and,

[0111] each R c and R d independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6 alkyl, or C1-C6 haloalkyl;

[0112] or R c and R d together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6 alkyl, or C1-C6 haloalkyl.

[0113] In some embodiments, the compound of Formula (I) is of Formula (la), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0114] independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6 alkyl, or C1-C6 haloalkyl;

[0115] In some embodiments, the compound of Formula (I) is of Formula (Ib), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0116]

[0117] In some embodiments, the compound of Formula (I) is of Formula (Ic), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0118]

[0119] In some embodiments, the compound of Formula (I) is of Formula (Id), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0120]

[0121] In some embodiments, the compound of Formula (I) is of Formula (Ie), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0122]

[0123] In some embodiments, the compound of Formula (I) is of Formula (If), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0124]

[0125] In some embodiments, the compound of Formula (I) is of Formula (Ig), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0126]

[0127] In some embodiments, the compound of Formula (I) is of Formula (Ih), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0128]

[0129] In some embodiments, the compound of Formula (I) is of Formula (Ii), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0130]

[0131] In some embodiments, the compound of Formula (I) is of Formula (Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0132]

[0133] In some embodiments, the compound of Formula (I) is of Formula (Ik) or Formula (Il), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0134]

[0135] wherein at least each R is independently H or D, and at least one of R is D.

[0136] In some embodiments, the compound of Formula (I) is of Formula (Im) or Formula (In), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0137]

[0138] wherein at least each R is independently H or D, and at least one of R is D.

[0139] In some embodiments, the compound of Formula (I) is of Formula (Io) or Formula (Ip), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0140]

[0141] wherein at least each R is independently H or D, and at least one of R is D.

[0142] In some embodiments, the compound of Formula (I) is of Formula (Iq) or Formula (Ir), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0143]

[0144] wherein at least each R is independently H or D, and at least one of R is D.

[0145] In some embodiments, the compound of Formula (I) is of Formula (Is) or Formula (It), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0146]

[0147] wherein at least each R is independently H or D, and at least one of R is D.

[0148] In some embodiments of the compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring A is heteroaryl, and ring B is cycloalkyl or heterocycloalkyl.

[0149] In some embodiments of the compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring A is aryl or heteroaryl, and ring B is heterocycloalkyl.

[0150] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring A is aryl or heteroaryl, and ring B is 5- to 8-membered cycloalkyl.

[0151] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring B is 5- to 6-membered cycloalkyl.

[0152] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring B is 5-membered cycloalkyl.

[0153] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring B is 5- to 6-membered heterocycloalkyl.

[0154] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring B is 5-membered heterocycloalkyl.

[0155] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring B is tetrahydrofuran or pyrrolidine. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring B is tetrahydrofuran.

[0156] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring A is bicyclic heteroaryl. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring A is indolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzothiophenyl, benzothiazolyl, benzofuranyl, or benzoxazolyl.

[0157] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring A is monocyclic heteroaryl. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring A is pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0158] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring A is phenyl.

[0159] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Y 9 is N. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Y 9 is CR 9 In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 9 is hydrogen, deuterium, halogen, -CN, -OR b , -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 deuterium- substituted alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 9 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterium- substituted alkyl. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 9 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 9 is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 9 is hydrogen.

[0160] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Y 6 is N. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Y 6 is CR 6 In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 6 is hydrogen, deuterium, halogen, -CN, -OR b , -NR c Rd -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 6 is hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 6 is hydrogen, deuterium, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 6 is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 6 is hydrogen.

[0161] In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Y 3 is N. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Y 3 is CR 3 . In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 3 is hydrogen, deuterium, halogen, -OR b , -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 3It is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteralkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ij) or their pharmaceutically acceptable salts, stereoisomers, or solvates, R 3 It is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ij) or their pharmaceutically acceptable salts, stereoisomers, or solvates, R 3 It is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ij) or their pharmaceutically acceptable salts, stereoisomers, or solvates, R 3 It is hydrogen.

[0162] In some embodiments of compounds of formula (I) or (Ia)-(Ij) or their pharmaceutically acceptable salts, stereoisomers or solvates, Y 8 For N. In some embodiments of compounds of formula (I) or (Ia)-(Ij) or their pharmaceutically acceptable salts, stereoisomers or solvates, Y 8 For CR 8 In some embodiments of compounds of formula (I) or (Ia)-(Ij) or their pharmaceutically acceptable salts, stereoisomers, or solvates, R 8 For hydrogen, deuterium, halogen, -CN, -OR b -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 deuteralkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ij) or their pharmaceutically acceptable salts, stereoisomers, or solvates, R 8 It is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteralkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ij) or their pharmaceutically acceptable salts, stereoisomers, or solvates, R 8 It is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ij) or their pharmaceutically acceptable salts, stereoisomers, or solvates, R 8 It is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ij) or their pharmaceutically acceptable salts, stereoisomers, or solvates, R 8 It is hydrogen.

[0163] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 4 is hydrogen, Ci-C6alkyl, Ci-C6haloalkyl, or Ci-C6deuteroalkyl. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 4 is Ci-C6alkyl or Ci-C6deuteroalkyl.

[0164] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 5 is hydrogen, Ci-C6alkyl, Ci-C6haloalkyl, or Ci-C6deuteroalkyl.

[0165] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 5 is Ci-C6alkyl or Ci-C6deuteroalkyl. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 5 is hydrogen.

[0166] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, W is -S-. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, W is -O-.

[0167] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, W is -NR 7 -. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 7 is hydrogen or Ci-C6alkyl. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 7 is hydrogen. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 7 is Ci-C6alkyl.

[0168] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each RA independently deuterium, halogen, -CN, -OR b , -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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R A1 substituents. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R A is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R A1 substituents. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R A is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, aryl, or heteroaryl; wherein each alkyl, aryl, and heteroaryl is independently optionally substituted with one or more R A1 substituents. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R A is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R A is independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R A is independently C1-C6 deuterated alkyl.

[0169] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R A1 is independently deuterium, halogen, -CN, -OR b , -NRc R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R A1 is independently deuterium, halogen, -CN, -OR b , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R A1 is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R A1 is independently deuterium, halogen, or C1-C6 alkyl.

[0170] In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 0-2. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 0 or 1. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 1 or 2. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 0. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 1. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 2. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 3.

[0171] In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R B is independently deuterium, halogen, -CN, -OR b , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R B1 . In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R B is independently deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R B1 . In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R B is independently deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, aryl, or heteroaryl; wherein each alkyl, aryl, and heteroaryl is independently optionally substituted with one or more R B1 . In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R B is independently deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R B is independently C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R B is independently C1-C6alkyl.

[0172] In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each RB1 independently deuterium, halogen, -CN, -OR b , -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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R B1 independently deuterium, halogen, -CN, -OR b , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R B1 independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R B1 independently deuterium, halogen, or C1-C6 alkyl.

[0173] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 0-2. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 0 or 1. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 1 or 2. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 0. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 1. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 2. In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 3.

[0174] In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C4alkylene; wherein one carbon atom is optionally substituted with a heteroatom selected from oxygen, sulfur, or nitrogen; and wherein L is optionally substituted with one or more R L In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C4alkylene; wherein one carbon atom is optionally substituted with a heteroatom selected from oxygen, sulfur, or nitrogen; and wherein L is optionally substituted with one or more R L In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C4alkylene; wherein one carbon atom is optionally substituted with a heteroatom selected from oxygen, sulfur, or nitrogen; and wherein L is optionally substituted with one or more R L In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C4alkylene; wherein one carbon atom is optionally substituted with a heteroatom selected from oxygen, sulfur, or nitrogen; and wherein L is optionally substituted with one or more R L In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C4alkylene; wherein one carbon atom is optionally substituted with a heteroatom selected from oxygen, sulfur, or nitrogen; and wherein L is optionally substituted with one or more R L In some embodiments of the compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C4alkylene; wherein one carbon atom is optionally substituted with a heteroatom selected from oxygen, sulfur, or nitrogen; and wherein L is optionally substituted with one or more R

[0175] In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C4alkylene; wherein one carbon atom is substituted with one oxygen; and wherein L is optionally substituted with one or more R L substituents.

[0176] In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C3alkylene; wherein one carbon atom is optionally substituted with a heteroatom selected from oxygen, sulfur, or nitrogen; and wherein L is optionally substituted with one or more R L substituents. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C3alkylene; wherein one carbon atom is optionally substituted with a heteroatom selected from oxygen or sulfur; and wherein L is optionally substituted with one or more R L substituents. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C3alkylene; wherein one carbon atom is optionally substituted with an oxygen atom; and wherein L is optionally substituted with one or more R L substituents. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C3alkylene; wherein one carbon atom is substituted with a heteroatom selected from oxygen, sulfur, or nitrogen; and wherein L is optionally substituted with one or more R L substituents. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C3alkylene; wherein one carbon atom is substituted with a heteroatom selected from oxygen or sulfur; and wherein L is optionally substituted with one or more R L substituents. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C3alkylene; wherein one carbon atom is optionally substituted with an oxygen atom; and wherein L is optionally substituted with one or more R L substituents.

[0177] In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C3alkylene; wherein one carbon atom is optionally substituted with a heteroatom selected from oxygen, sulfur, or nitrogen; and wherein L is optionally substituted with one or more R Lsubstituted. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C3alkylene; wherein one carbon atom is optionally substituted with a heteroatom selected from oxygen or sulfur; and wherein L is optionally substituted with one or more R L substituted. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C3alkylene; wherein one carbon atom is optionally substituted with a heteroatom selected from oxygen or sulfur; and wherein L is optionally substituted with one or more R L substituted. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C3alkylene; wherein one carbon atom is optionally substituted with a heteroatom selected from oxygen or sulfur; and wherein L is optionally substituted with one or more R L substituted. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C3alkylene; wherein one carbon atom is optionally substituted with a heteroatom selected from oxygen or sulfur; and wherein L is optionally substituted with one or more R L substituted. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C3alkylene; wherein one carbon atom is optionally substituted with a heteroatom selected from oxygen or sulfur; and wherein L is optionally substituted with one or more R L substituted. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C3alkylene; wherein one carbon atom is optionally substituted with a heteroatom selected from oxygen or sulfur; and wherein L is optionally substituted with one or more R

[0178] substituted. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C3alkylene; wherein one carbon atom is optionally substituted with a heteroatom selected from oxygen or sulfur; and wherein L is optionally substituted with one or more R L substituted. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C3alkylene; wherein one carbon atom is optionally substituted with a heteroatom selected from oxygen or sulfur; and wherein L is optionally substituted with one or more R L substituted. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C3alkylene; wherein one carbon atom is optionally substituted with a heteroatom selected from oxygen or sulfur; and wherein L is optionally substituted with one or more R L substituted. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C3alkylene; wherein one carbon atom is optionally substituted with a heteroatom selected from oxygen or sulfur; and wherein L is optionally substituted with one or more R Lsubstituted. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2alkylene; wherein one carbon atom is substituted with a heteroatom selected from oxygen or sulfur; and wherein L is optionally substituted with one or more R L substituted. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2alkylene; wherein one carbon atom is substituted with an oxygen atom; and wherein L is optionally substituted with one or more R L substituted.

[0179] In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R L is independently deuterium, halogen, -CN, -OR b , -NR c R d , -C(=O)R a , C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl; or two R L on the same carbon are taken together to form oxo, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R L is independently deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; or two R L on the same carbon are taken together to form oxo, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R L is independently deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl.

[0180] In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is -CH2-O-, -O-CH2-, -CH2-S-, or -S-CH2-. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is -CH2-O- or -O-CH2-.

[0181] In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R aindependently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R a independently C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of the above compounds, each R a is independently C1-C6alkyl.

[0182] In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R b independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R b independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of the above compounds, each R b is independently hydrogen or C1-C6alkyl. In some embodiments of the above compounds, each R b is hydrogen. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R b is independently C1-C6alkyl.

[0183] In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R c and R dindependently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R c and R d are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R c and R d are independently hydrogen or C1-C6alkyl. In some embodiments of the above compounds, each R c and R d is hydrogen. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R c and R d are independently C1-C6alkyl.

[0184] In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each L, R A , R B , R 4 , R a , R b , R c and R d are independently substituted with one, two, three, or four substituents as defined herein. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each L, R A , R B , R 4 , R a , R b , R c and R d are independently optionally substituted with one, two, or three substituents as defined herein. In some embodiments of a compound of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each L, R A , R B , R 4 , R a , R b , Rc and R d independently optionally substituted by one or two substituents as defined herein. In some embodiments of the compounds of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each L, R A , R B , R 4 , R a , R b , R c and R d is independently optionally substituted by one substituent as defined herein.

[0185] In some embodiments of the compounds of Formula (I) or (la)-(lj), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, the compound is selected from:

[0186]

[0187]

[0188]

[0189] or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0190] Other forms of the compounds disclosed herein

[0191] Isomers / stereoisomers

[0192] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as their mixtures. In some cases, the compounds described herein have one or more chiral centers and each center occurs in the R- or S-configuration. The compounds described herein include all diastereomers, enantiomers and epimers, and mixtures thereof. In other embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers 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 their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereoisomers have different physical properties (e.g., melting points, boiling points, solubilities, reactivities, etc.) and are separated by exploiting these differences. In some embodiments, the diastereoisomers are separated by chiral chromatography, or preferably by separation / re-dissolution techniques based on solubility differences. In some embodiments, the optically pure enantiomers are then recovered with the resolving agent.

[0193] Labeled compounds

[0194] In some embodiments, the compounds described herein exist in their isotopically-labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically-labeled compounds as a pharmaceutical composition. Accordingly, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those described herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein or a solvate or stereoisomer thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and36 Cl. Compounds described herein, and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, comprising isotopes of the above-mentioned isotopes and / or other atoms are included within the scope of this disclosure. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3 H and 14 C 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. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, isotopically labeled compounds or pharmaceutically acceptable salts, solvates, or stereoisomers thereof are prepared by any suitable method.

[0195] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0196] pharmaceutically acceptable salt

[0197] In some embodiments, the compounds described herein exist in the form of a pharmaceutically acceptable salt thereof. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt as a pharmaceutical composition.

[0198] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with any of a number of inorganic or organic acids and bases, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting the purified compound in its free form with a suitable acid or base and isolating the salt thus formed.

[0199] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with inorganic acids, organic acids, or inorganic bases, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, besylate, bisulfate, bisulfite, bromide, butyrate, butyne-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, mesylate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propylsulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, and xylene sulfonate.

[0200] Further, the compounds described herein can be prepared by reacting the free base form of the compound with pharmaceutically acceptable inorganic or organic acids, including but not limited to, inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like; and organic acids such as acetic, propionic, hexanoic, cyclopentanepropionic, glycolic, pyruvic, lactic, malonic, succinic, malic, maleic, fumaric, p-toluene sulfonic, tartaric, trifluoroacetic, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, cinnamic, mandelic, arylsulfonic, methanesulfonic, ethanesulfonic, 1,2-ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 2-naphthalenesulfonic, 4-methylbicyclo- [2.2.2]oct-2-ene-1-carboxylic, glucoheptonic, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic), 3-phenylpropionic, trimethylacetic, tertiary butylacetic, lauryl sulfuric, gluconic, glutamic, hydroxynaphthoic, salicylic, stearic, and muconic acids.

[0201] In some embodiments, those compounds described herein that contain a free acid group are reacted with a suitable base such as the hydroxide, carbonate, bicarbonate or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary or quaternary amine. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium salts, and aluminum salts, among others. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl)4, and the like.

[0202] Representative organic amines which can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include quaternized

[0203] solvate

[0204] In some embodiments, the compounds described herein exist as solvates. The present disclosure provides methods of treating diseases by administering such solvates. The present disclosure also provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0205] Solvates include stoichiometric or non-stoichiometric amounts of solvent, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is an alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated and solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

[0206] tautomers

[0207] In certain instances, compounds exist as tautomers. The compounds described herein include all possible tautomers of the chemical formulae described herein. Tautomers are compounds that can be interconverted by a migration of a hydrogen atom accompanied by a switching of a single and adjacent double bond. Chemical equilibria of tautomers can exist in bonding arrangements where tautomerization is possible. All tautomeric forms of the compounds disclosed herein are contemplated. The exact proportions of tautomers will depend on several factors, including temperature, solvent, and pH.

[0208] Preparation of compounds

[0209] Compounds used in the reactions described herein were prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or chemicals described in the chemical literature. "Commercially available chemicals" were obtained from standard commercial sources, e.g. Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Harpak, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Wattby, CT), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Products, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0210] Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of the compounds described herein, or provide references to articles that describe such preparations, include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley Interscience, New York, 1992. Other suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of the compounds described herein, or provide references to articles that describe such preparations, also include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3 527-29074-5; Hoffman, R. V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J."Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T.W.G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0211] Particular and exemplary reactants can be identified, optionally, by reference to the Index of Known Chemicals prepared by the American Chemical Society's Chemical Abstracts Service, which is available in most public and university libraries and online. Chemicals that are known but not commercially available can be prepared by custom chemical synthesis companies, many of which standard chemical supply companies (such as those listed above) offer custom synthesis services. References for the preparation and selection of pharmaceutically acceptable salts of the compounds described herein are P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0212] Pharmaceutical compositions

[0213] In certain embodiments, the compounds described herein are administered as pure chemicals. In some embodiments, the compounds described herein are combined with a selected pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier), the selection of which is based on the selected route of administration and standard pharmaceutical practice, e.g., as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21stedition, Mack Pub. Co., Easton, PA (2005)). st

[0214] Accordingly, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0215] In certain embodiments, the compounds provided herein are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, e.g., unreacted intermediates or synthetic byproducts produced, e.g., in one or more steps of a synthetic method.

[0216] ​The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented). The appropriate dose and the appropriate duration and frequency of administration will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration, among others. Generally, the appropriate dose and treatment regimen provides the composition in an amount sufficient to provide a therapeutic and / or prophylactic benefit (e.g., improved clinical outcome, such as more frequent complete or partial remissions, or longer periods of disease- free and / or overall survival, or reduction in severity of symptoms). Optimal doses usually are determined using experimental models and / or clinical trials. Optimal doses depend on the physical mass, weight, or blood volume of the patient.

[0217] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and epidural, and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ocular administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated as a tablet, pill, capsule, liquid, inhalant, nasal spray, suppository, suspension, gel, colloid, dispersion, suspension, solution, emulsion, ointment, emulsion, eye drop, or ear drop. In some embodiments, the pharmaceutical composition is formulated as a tablet.

[0218] Suitable dosages and dosage regimens are determined by techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages less than the optimum dose of the compounds disclosed herein. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In some embodiments, the present methods involve administering about 0.1 pg to about 50 mg of at least one compound described herein per kg of body weight of the subject. For a 70 kg patient, dosages of about 10 pg to about 200 mg of the compounds disclosed herein will be more commonly used, depending on the physiological response of the subject.

[0219] By way of example only, a dose of a compound described herein for use in a method of treating a disease described herein is about 0.001 to about 1 mg / kg body weight of the subject per day, for example about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg / kg body weight per day. In some embodiments, a dose of a compound described herein for use in the methods is about 1 to about 1000 mg / kg body weight of the subject being treated per day, for example about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.

[0220] Methods of treatment

[0221] The compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, can be used to inhibit the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by the compounds and methods is TYK2.

[0222] The compounds provided herein are inhibitors of TYK2 and are therefore useful for treating one or more diseases associated with the activity of TYK2 or a mutant thereof.

[0223] Provided herein are methods of treating a disease or disorder, wherein the disease or disorder is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a disease associated with transplantation, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0224] In some embodiments, the disease or disorder is an autoimmune disease. In some embodiments, the disease or disorder is selected from the group consisting of type 1 diabetes mellitus, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behcet’s disease, POEMS syndrome, Crohn’s disease, ulcerative colitis, and inflammatory bowel disease.

[0225] In some embodiments, the disease or disorder is an inflammatory disease. In some embodiments, the inflammatory disease is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn’s disease, ulcerative colitis, inflammatory bowel disease.

[0226] In some embodiments, the disease or disorder is a proliferative disease. In some embodiments, the proliferative disease is cancer. In some embodiments, the disease or disorder is a proliferative disease. In some embodiments, the proliferative disease is a blood cancer. In some embodiments, the proliferative disease is leukemia. In some embodiments, the leukemia is T cell leukemia. In some embodiments, the T cell leukemia is T cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disease is polycythemia vera, primary myelofibrosis, or thrombocythemia.

[0227] In some embodiments, the disease or disorder is an endocrine disease. In some embodiments, the endocrine disease is polycystic ovary syndrome, Crouzon's syndrome, or type 1 diabetes.

[0228] In some embodiments, the disease or disorder is a neurological disease. In some embodiments, the neurological disease is Alzheimer's disease.

[0229] In some embodiments, the proliferative disease is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation in the FERM domain, the JH2 domain, or the kinase domain. In some embodiments, the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[0230] In some embodiments, the disease or disorder is associated with transplantation. In some embodiments, the disease or disorder associated with transplantation is transplant rejection or graft versus host disease.

[0231] In some embodiments, the disease or disorder is associated with Type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments, the disease or disorder is associated with Type I interferon signaling. In some embodiments, the disease or disorder is associated with IL-10 signaling. In some embodiments, the disease or disorder is associated with IL-12 signaling. In some embodiments, the disease or disorder is associated with IL-23 signaling.

[0232] Provided herein are methods of treating a skin inflammatory or allergic disorder, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne vulgaris, and other skin inflammatory or allergic diseases.

[0233] Provided herein are methods of treating other diseases or conditions, such as diseases or conditions with an inflammatory component, for example, treating ocular diseases and conditions such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis and inflammatory diseases in which an autoimmune reaction is implicated or has an autoimmune component or etiology, including autoimmune hematological diseases (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontal disease, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca, and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis, cryopyrin-associated periodic syndromes, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome, e.g., including idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospiral nephritis, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle atrophy, catabolic disorders, obesity, fetal growth retardation,Hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, familial periodic fever syndrome, (allergic and non-allergic, mild, moderate, severe, bronchitic and exercise-induced) asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, ocular allergy, silica-induced disease, chronic obstructive pulmonary disease (reducing injury, airway inflammation, bronchial hyperreactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, flat pemphigus, type 1 diabetes or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonitis, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0234] In some embodiments, the inflammatory disease is acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndromes (CAPS), or osteoarthritis.

[0235] In some embodiments, the inflammatory disease is a Thl or Thl 7-mediated disease. In some embodiments, the Thl 7-mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0236] In some embodiments, the inflammatory disease is Sjogren's syndrome, an allergic disease, osteoarthritis, an ocular condition such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, or a disease affecting the nose such as allergic rhinitis.

[0237] Combination therapy

[0238] In certain instances, a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with a second therapeutic agent. In some embodiments, the patient experiences an increased benefit by the administration of one of the compounds described herein with a second therapeutic agent (which also includes a therapeutic regimen) that also has a therapeutic benefit.

[0239] In a particular embodiment, a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, and thus provide a greater overall benefit than either therapeutic agent administered alone.

[0240] In any case, regardless of the disease, disorder, or condition being treated, the patient experiences an overall benefit greater than with either therapeutic agent alone, or the patient experiences a synergistic benefit.

[0241] In certain embodiments, when a compound disclosed herein is administered in combination with a second therapeutic agent, a different therapeutically effective dose of the compound disclosed herein will be used in formulating the pharmaceutical composition and / or in the therapeutic regimen. Therapeutically effective doses of drugs and other agents used in combination regimens are optionally determined by methods analogous to those set forth above for the active agents themselves. In addition, the prophylactic / treatment methods described herein include the use of metronomic dosing, i.e., the provision of more frequent, lower doses to minimize toxic side effects. In some embodiments, a combination therapy regimen includes a therapy regimen in which administration of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is initiated prior to, during, or following treatment with a second agent described herein, and continues during treatment with the second agent or for any period following termination of treatment with the second agent. It also includes therapies in which the compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered simultaneously, or not simultaneously, and / or at reduced or increased intervals, with the second agent used in combination during the course of therapy. Combination therapy also includes periodic therapy that is initiated and stopped at different times to assist in the clinical management of the patient.

[0242] It will be appreciated that dosage regimens for treating, preventing, or ameliorating a disorder for which relief is sought are adjusted in accordance with a variety of factors (e.g., the disease, disorder, or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, the dose regimen actually employed will in some cases vary according to the dosage regimen described herein and in some embodiments will deviate from the dosage regimen described herein.

[0243] For the combination therapies described herein, the dosage of a coadministered compound varies depending on the type of combination drug employed, on the particular drug employed, on the disease or condition being treated, and the like. In further embodiments, when coadministered with a second therapeutic agent, the compounds provided herein are administered simultaneously or sequentially with the second therapeutic agent.

[0244] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents are provided, by way of example only, in a single, unified form or in multiple forms (e.g., as a single pill or as two separate pills).

[0245] The compounds described herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, and combination therapies are administered before, during, or after the occurrence of a disease or condition, and the timing of administration of the compositions comprising the compounds varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to a subject who is predisposed to developing a disease or condition to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of symptoms. In particular embodiments, the compounds described herein are administered as soon as possible after the onset of the disease or condition is detected or suspected, and for the length of time required to treat the disease. In some embodiments, the length of time required for treatment varies, and the length of treatment is adjusted to suit the particular needs of each subject. For example, in particular embodiments, the compounds described herein, or formulations comprising the compounds, are administered for at least 2 weeks, about 1 month to about 5 years.

[0246] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are administered in conjunction with an adjuvant. In one embodiment, the therapeutic effect of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., the adjuvant itself has minimal therapeutic benefit but, when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Examples

[0247] Intermediate 1

[0248]

[0249] First Step: Intermediate 1b

[0250] To a solution of intermediate la (84 g, 363.6 mmol) in EtOH (464 mL) and concentrated HCL (116 mL) was added SnCl2(408 g, 2.16 mol). The reaction mixture was stirred at 60 °C for 3 h under nitrogen. After cooling to room temperature, the mixture was poured into 2 M aqueous NaOH (750 mL) at 0 °C to pH = 12. To the mixture was added DCM (800 mL), and the white solid was removed by filtration. The organic layer was separated, and the aqueous phase was extracted with DCM (500 mL*2). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography on silica gel (petroleum ether / EtOAc = 2 / 1) to give the product intermediate lb as a yellow solid (49 g, 67% yield). LCMS [M+1] + = 201.2.

[0251] Step 2: Intermediate lc

[0252] A solution of intermediate lb (49 g, 243.8 mmol) in AcOH (530 mL) and H2O (100 mL) was cooled to 0 °C, then NaNO2(13.36 g, 193.6 mmol) in water (167 mL) was added. The reaction mixture was stirred at room temperature for 30 min. After completion, yellow precipitate was observed to form gradually. The solid was collected by filtration and washed with 65% aqueous AcOH, concentrated to give the product intermediate lc as a yellow solid (40.7 g, 78% yield). LCMS [M+1] + = 212.2.

[0253] Step 3: Intermediate Id, intermediate Id', and intermediate Id"

[0254] To a solution of intermediate lc (2.0 g, 9.48 mmol) in THF (13 mL) was added NaH (545 mg, 14.2 mmol) and CD3I (2.75 g, 18.96 mmol). The reaction mixture was stirred at 0 °C to room temperature for 16 h. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated. The crude product was purified by flash column chromatography on silica gel (petroleum ether / DCM = 1 / 1) to give the product intermediate Id (800 mg, 24% yield, retention time: 1.48 min) as a white solid, intermediate Id' (400 mg, 18% yield, retention time: 1.42 min) as a white solid, and intermediate Id" (500 mg, 25% yield, retention time: 1.33 min) as a white solid. LCMS [M+1] + = 229.2.

[0255] Step 4: Intermediate 1

[0256] To a solution of intermediate 1d (800 mg, 3.5 mmol) in CC14(10 mL) was added NBS (935 mg, 5.25 mmol) and AIBN (287 mg, 1.75 mmol). The reaction mixture was stirred at 80 °C overnight. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography on silica gel (petroleum ether / DCM = 1 / 1) to provide the product intermediate 1 (700 mg, 65% yield) as a white solid. LCMS [M+1] + = 306.2.

[0257] Example 1 : General synthetic procedure for example 1

[0258]

[0259] Step 1 : Example 1 b

[0260] To a solution of example 1 a (5.0 g, 36.34 mmol) and Et3N (5.52 g, 54.50 mmol) in DCM (100 mL) was added Boc20 (9.52 g, 43.60 mmol) at 0 °C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated and the crude product was purified by column chromatography eluting with DCM:MeOH (3-5%) to afford example 1 b (5.0 g, 68% yield) as a white solid. LCMS [M-Boc+1] + = 102.1.

[0261] Step 2: Example 1 d

[0262] To a solution of example 1 b (300 mg, 1.49 mmol) in THF (3 mL) was added intermediate 1 (459 mg, 1.49 mmol), TBAI (55 mg, 0.149 mmol) and NaH (72 mg, 1.79 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3 h. H20 (100 mL) was added and the mixture was extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine (30 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with petroleum ether / EtOAc (60 / 40) to afford example 1 d (0.3 g, 92% yield) as a yellow oil. LCMS [M-2Boc+1] + = 328.1.

[0263] Step 3: Example 1 e

[0264] To a solution of Example 1d (0.3 g, 0.72 mmol) in dioxane (3 mL) was added Pd2(dba)3(66 mg, 0.0723 mmol), XantPhos (84 mg, 0.14 mmol), CS2CO3(707 mg, 2.17 mmol), and NH2Boc (127 mg, 1.09 mmol). The reaction mixture was degassed with argon for 3 times and stirred at 100 °C for 3 h. The reaction mixture was poured into water (100 mL). The mixture was extracted with DCM (50 mL*3). The combined organic layers were washed with brine (50 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with MeOH / DCM (5%~10%) to give Example 1e (0.3 g, yield 47%) as colorless oil. LCMS [M-Boc+1] + = 265.2.

[0265] Step 4: Example 1f

[0266] To a solution of Example 1e (0.3 g, 0.645 mmol) in DCM (5 mL) was added TFA (2.58 g, 22.60 mmol) at room temperature. The resulting solution was stirred at room temperature for 1 h. The mixture was concentrated in vacuum. The pH of the residue was adjusted to 9 with 1 M NaHC03. After that, the mixture was extracted with DCM (50 mL*3). The combined organic layers were washed with brine (50 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated. The solvent was removed in vacuum. Example 1f residue (0.17 g, yield 100%) was obtained as yellow oil which was used in the next step without further purification. LCMS [M-Boc+1] + = 265.2.

[0267] Step 5: Example 1h

[0268] To a solution of Example 1f (0.16 g, 0.61 mmol) in DCM (6 mL) was added DIEA (469 mg, 3.63 mmol), Example 1g (198 mg, 0.61 mmol) and HATU (230 mg, 0.61 mmol). The reaction mixture was stirred at room temperature for 1 h. Water (30 mL) was added, and the mixture was extracted with DCM (10 mL*3). The combined organic layers were washed with brine (10 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography eluting with MeOH / DCM (7%) to give Example 1h (0.11 g, yield 11%) as colorless solid. LCMS [M+1] + = 573.2.

[0269] Step 6: Example 1i

[0270] To a solution of Example 1h (0.1 g, 0.17 mmol) in dioxane (1 mL) was added t-BuXphos Pd G3 (28 mg, 0.035 mmol) and CS2CO3 (171 mg, 0.52 mmol). The reaction mixture was degassed with argon 3 times and stirred at 100 °C for 75 min. Water (50 mL) was added, and the mixture was extracted with DCM (30 mL*3). The combined organic layers were washed with brine (30 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography eluting with MeOH / DCM (6%) to give Example 1i (0.1 g, yield: quantitative) as a yellow solid. LCMS [M+1] = 537.3. +

[0271] Step 7: Example 1

[0272] To a solution of Example 1i (0.1 g, 0.19 mmol) in DCM (1 mL) was added TFA (531 mg, 4.66 mmol) at room temperature. The resulting solution was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The pH of the residue was adjusted to 9 with 1 M NaHC03. After that, the mixture was extracted with DCM (50 mL*3). The combined organic layers were washed with concentrated brine (50 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Pre-TLC (MeOH / DCM = 10%) to give Example 1 (3.1 mg, yield 3.8%) as a white solid. LCMS [M+1] = 437.3. + 1 H NMR (400 MHz, DMSO-d6) d 9.94 (s, 1H), 9.20 (d, J = 4.6 Hz, 1H), 8.14 (s, 1H), 7.84 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 5.2 Hz, 1H), 7.30 (s, 1H), 6.40 (s, 1H), 4.94 (d, J = 14.6 Hz, 1H), 4.60 (d, J = 14.5 Hz, 1H), 3.83 (s, 1H), 3.73 (t, J = 8.4 Hz, 1H), 2.91 (d, J = 4.8 Hz, 3H), 2.27 (d, J = 10.3 Hz, 1H), 2.14 - 1.93 (m, 2H), 1.72 (d, J = 10.6 Hz, 1H), 1.61 - 1.42 (m, 2H).

[0273] Example A. TYK2 JH2 domain binding assay

[0274] The binding constants of the compounds described herein against the JH2 domain were determined by the following assay for​​ Protocol assay for the assay (DiscoveRx). A fusion protein of a partial length construct of human TYK2 (JH2 domain-pseudokinase) (amino acids G556 to D888 based on reference sequence NP_003322.3) and the DNA binding domain of NFkB was expressed in transiently transfected HEK293 cells. From these HEK293 cells, extracts were prepared in M-PER extraction buffer (Pierce) in the presence of Protease Inhibitor Cocktail Complete (Roche) and Phosphatase Inhibitor Cocktail Set II (Merck) according to the manufacturer's instructions. The TYK2 (JH2 domain-pseudokinase) fusion protein was tagged with a chimeric double-stranded DNA tag comprising an NFkB binding site fused to an amplicon for qPCR readout, which was directly added to the expression extract (final concentration of DNA tag in the binding reaction was 0.1 nM).

[0275] Streptavidin-coated magnetic beads (Dynal M280) were treated with biotinylated small molecule ligand for 30 min at room temperature to generate the affinity resin for the binding assay. Ligand beads were blocked with an excess of biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and reduce non-specific binding.

[0276] Binding reactions were assembled by combining 16 μΐ of DNA-tagged kinase extract, 3.8 μΐ of ligand affinity beads, and 0.18 μΐ of test compound (PBS / 0.05% Tween 20 / 10 mM DTT / 0.1% BSA / 2 μg / ml sonicated salmon sperm DNA). The extract was used directly in the binding assay without any enzyme purification steps, and the stock solutions were diluted a total of >10,000-fold (final DNA-tagged enzyme concentration <0.1 nM). The extract was loaded with DNA tag and diluted into the binding reaction in a two-step process. First, the extract was diluted 1 : 100 in lx binding buffer (PBS / 0.05% Tween 20 / 10 mM DTT / 0.1% BSA / 2 μg / ml sonicated salmon sperm DNA) containing 10 nM DNA tag. This dilution was allowed to equilibrate at room temperature for 15 minutes, then diluted 1 : 100 in lx binding buffer. Test compounds were prepared as 111 x stocks in 100% DMSO. Kd was determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements were distributed in 100% DMSO by acoustic transfer (non-contact dispensing). Compounds were then diluted directly into the assay such that the final concentration of DMSO was 0.9%. All reactions were performed in polypropylene 384-well plates. The final volume was 0.02 mL each. Assay samples were incubated for 1 hour at room temperature with shaking. The beads were then pelleted and washed with wash buffer (lx PBS, 0.05% Tween 20) to remove displaced kinase and test compound. The washed beads were resuspended in elution buffer (lx PBS, 0.05% Tween 20, 0.5 μΜ non-biotinylated affinity ligand) and incubated for 30 minutes at room temperature with shaking. The concentration of kinase in the eluate was measured by qPCR. The qPCR reaction was assembled by adding 2.5 μΐ of kinase eluate to 7.5 μΐ of qPCR master mix containing 0.15 μΜ of amplicon primer and 0.15 μΜ of amplicon probe. The qPCR program included a hot start at 95 °C for 10 minutes followed by 35 cycles of 95 °C for 15 seconds and 60 °C for 1 minute.

[0277] Test compounds were prepared as 111 x stocks in 100% DMSO. Kd was determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements were distributed in 100% DMSO by acoustic transfer (non-contact dispensing). Compounds were then diluted directly into the assay such that the final concentration of DMSO was 0.9%. The highest concentration of compound used was 30,000 nM to determine Kd. Kd measurements were set up in duplicate.

[0278] Binding constants (Kd) were calculated using the Hill equation from standard dose-response curves:

[0279] Response = Background + (Signal - Background) / [1 + (Kd Hill坡度 / Dose Hill坡度 )

[0280] The Hill Slope was set to -1. The curve was fitted using a non-linear least squares method with the Levenberg-Marquardt algorithm (Levenberg, K., A method for the solution of certain non-linear problems in least squares, Q. Appl. Math. 2, 164-168 (1944)).

[0281] The results are shown in Table 1:

[0282] Table 1

[0283]

[0284] Example B: INFa induces pSTAT5 in human PBMCs

[0285] Fresh human PBMCs were resuspended in RPMI 1640 medium containing 10% FBS. Cells were seeded in a round-bottom 96-well plate at a concentration of 200,000 cells / well. A 10-point dilution series of test compounds (top dose 10 uM, 1 :5 dilution) was added to the wells using a liquid dispenser (Tecan D300e) and incubated for 1 hour at 37°C. Human INFa recombinant protein (R&D Systems) was then added to the wells at a final concentration of 5000 units / ml and incubated for 15 minutes at 37°C. Cell lysates were prepared and analyzed by the Phospho STAT5 (Tyr693) kit (Meso Scale Discovery) following the manufacturer's protocol.

[0286] For calculation of inhibition, relative pSTAT5 signal per well = pSTAT5 signal per well - average pSTAT5 signal of baseline.

[0287] % inhibition = (average pSTAT5 signal of INFa treated wells - relative value of pSTAT5 signal in each compound containing well) / average pSTAT5 signal of INFa treated wells * 100%

[0288] The curves were plotted as % inhibition (y-axis) vs. compound concentration (x-axis) and fitted as log(inhibitor) vs. normalized response - variable slope of GraphPad Prism 7.0.

[0289] Control is BMS-986165:

[0290]

[0291] The results are shown in Table 2.

[0292] Table 2

[0293] Ex. p-STAT5 IC50 (nM) IC50 relative to control 1 1.7 1.1

[0294] Example C: Pharmaceutical Composition

[0295] Example CI: Parenteral Composition

[0296] To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water-soluble salt of a compound described herein is dissolved in DMSO, and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for injection administration.

[0297] Example C2: Oral Composition

[0298] To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound described herein is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit suitable for oral administration, such as a hard gelatin capsule.

[0299] Example C3: Sublingual (Hard Lozenge) Composition

[0300] To prepare a pharmaceutical composition for oral delivery, such as a hard lozenge, 100 mg of a compound described herein is mixed with 420 mg of mixed powdered sugar, 1.6 mL of light corn syrup, 2.4 mL of distilled water, and 0.42 mL of peppermint extract. The mixture is gently mixed and poured into a mold to form lozenges suitable for oral administration.

[0301] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes in light thereof will be included within the purview of the disclosure and scope of the appended claims.

Claims

1. A compound of Formula (la) or Formula (If) or a pharmaceutically acceptable salt or stereoisomer thereof: Formula (Ia); formula (If), wherein: L is -CH2-O- or -O-CH2; Ring A is benzotriazolyl; Ring B is 5-membered cycloalkyl; R A independently at each occurrence selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, and C1-C6deuteroalkyl; n is 1 or 2; R B independently at each occurrence selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, and C1-C6deuteroalkyl; m is 0 or 1; Y 3 for CR 3 ; Y 6 for CR 6 ; Y 8 is N; Y 9 is N; R 3 and R 6 are independently selected from the group consisting of hydrogen, halogen and Ci-C6alkyl; R 4 Ci-C6alkyl or Ci-C6deuteroalkyl; R 5 is hydrogen; W is -NR 7 -; and R 7 is hydrogen or CrC6alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 6 is hydrogen.

3. The compound of claim 1 or 2 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 3 is hydrogen.

4. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 4 is C1-C6 alkyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 7 is hydrogen.

6. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Each R A It is independently a C1-C6 deuterated alkyl group.

7. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: n is 1.

8. The compound of claim 1, wherein the compound is selected from: 、 、 and or a pharmaceutically acceptable salt or stereoisomer thereof.

9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-8 or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

10. Use of a compound of any one of claims 1-8 or a pharmaceutically acceptable salt or stereoisomer thereof, for the manufacture of a medicament for the treatment of a TYK2-mediated disease.

11. The use of claim 10, wherein the TYK2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a disease associated with transplantation.

12. The use of claim 10, wherein the disease is associated with Type I Interferon, IL-10, IL-12, or IL-23 signaling.

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