TYK2 inhibitors and uses thereof

Abstract

Described herein are compounds of Formula (I) that are useful in treating a TYK2-mediated disease. In some embodiments, the TYK2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disorder, or a transplant-related disease. JPEG2023541203000049.jpg7999

Description

Related Applications

[0001]

[0001] 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. [Technical Field]

[0002]

[0002] Described herein are compounds, methods for making such compounds, pharmaceutical compositions and medicaments 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]

[0003] Background of the Invention

[0003] 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 for cytokine signaling. TYK2 interacts with the cytoplasmic domains of type I and type II cytokine receptors and interferon type I and type III receptors and is activated by these receptors upon cytokine binding. Cytokines involved in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as limitin)) and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin-1, cardiotrophin-like cytokine, and LIF). Activated TYK2 then phosphorylates further signaling proteins such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

[0004]

[0004] TYK2 activation by IL-23 is associated with inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. A genome-wide association study of 2,622 individuals with psoriasis confirmed the association between disease susceptibility and TYK2. TYK2 knockout or tyrophore inhibition significantly reduced both IL-23- and IL-22-induced dermatitis.

[0005] TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell hyperplasia (GCH) and mucus hypersecretion are mediated by IL-13-induced activation of TYK2, which in turn activates STAT6.

[0006]

[0006] Reduced TYK2 activity protects joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis. Mechanistically, reduced Tyk2 activity reduced the production of Th1 / Th17-associated cytokines and matrix metalloproteinases, as well as other important markers of inflammation.

[0007]

[0007] TYK2 knockout mice showed complete resistance to experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)) without infiltration of CD4 T cells in the spinal cord compared with controls. This suggests that TYK2 is essential for the progression of pathogenic CD4-mediated disease in MS. This supports earlier studies linking increased TYK2 expression to MS susceptibility. Loss-of-function mutations in TYK2 cause reduced demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelinating disorders.

[0008] TYK2 is the only signaling messenger common to both IL-12 and IL-23. TYK2 knockout reduced footpad thickness induced by methylated BSA injection, imiquimide-induced psoriasis-like skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice.

[0009]

[0009] Joint linkage and association studies of various type I IFN signaling genes in systemic lupus erythematosus (SLE, an autoimmune disease) have shown a strong and significant correlation between loss-of-function mutations in TYK2 and reduced prevalence of SLE in affected families. Genome-wide association studies of SLE individuals versus unaffected cohorts have shown a highly significant correlation between the TYK2 locus and SLE.

[0010] TYK2 has been shown to play an important role in maintaining tumor surveillance, and TYK2 knockout mice exhibited reduced cytotoxic T cell responses and accelerated tumor growth. However, these effects were associated with efficient inhibition of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors may be highly suitable for the treatment of autoimmune diseases or transplant rejection. While other JAK family members, such as JAK3, have similar roles in the immune system, TYK2 has been suggested as a superior target because it participates in fewer and more closely related signaling pathways and is therefore less likely to cause off-target effects.

[0011]

[0011] Studies in T-cell acute lymphoblastic leukemia (T-ALL) have shown that T-ALL is highly dependent on IL-10 via TYK2 through STAT1-mediated signal transduction to maintain cancer cell survival by upregulating the anti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, reduced cell proliferation. Specific activating mutations in TYK2 that promote cancer cell survival include those in the FERM domain (G36D, S47N, and R425H), JH2 domain (V731I), and kinase domain (E957D and R1027H). However, TYK2 enzymes characterized by kinase-dead mutations (M978Y or M978F) in addition to the activating mutation (E957D) were unable to transform, confirming that the kinase function of TYK2 is required for enhanced cancer cell survival.

[0012]

[0012] Therefore, selective inhibition of TYK2 has been suggested as a suitable target for patients with IL-10 and / or BCL2-dependent tumors, 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 (Aβ) peptide. Reduced TYK2 phosphorylation of STAT3 after Aβ administration leads to reduced neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer's patients.

[0013]

[0013] Inhibition of the JAK-STAT signaling pathway has also been implicated in hair growth and reversal of hair loss associated with alopecia areata.

[0014]

[0014] Therefore, compounds that inhibit the activity of TYK2, particularly those with superior selectivity over JAK2, would be beneficial. Such compounds should provide a pharmacological response that advantageously treats one or more of the conditions described herein without the side effects associated with inhibition of JAK2.

[0015]

[0015] Thus, there is a need to provide novel inhibitors that have more potent or advantageous pharmacologically important properties, such as selectivity over other JAK kinases, particularly JAK2. Summary of the Invention

[0016] BRIEF SUMMARY OF THE INVENTION

[0016] 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 disorder, or a transplant-related disease. In some embodiments, the TYK2-mediated disease is cancer.

[0017] Disclosed herein are compounds of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0018] [ka]

[0019] During the ceremony: L is C1-C4 alkylene; wherein one or two carbon atoms may optionally be replaced by a heteroatom selected from oxygen, sulfur, nitrogen, or phosphate; L optionally comprises one or more R L may be substituted with; Each R L are 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same carbon L taken together form oxo, cycloalkyl, or heterocycloalkyl; Ring A is heteroaryl and Ring B is cycloalkyl or heterocycloalkyl; Or ring A is aryl or heteroaryl and ring B is heterocycloalkyl or 5-8 membered cycloalkyl; Each R A are 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 deuteroalkyl, 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 independently and optionally is selected from the group consisting of one or more R A1 may be substituted with; Each R A1 are 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same carbon A1 together to form oxo; n is 0-4; Each R B are 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 deuteroalkyl, 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 independently and optionally is selected from the group consisting of one or more R B1 May be replaced by; or two R on the same carbon B together to form oxo; Each R B1 are 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)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-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same carbon B1 together to form oxo; m is 0-4;

[0020] [ka]

[0021] is a single or double bond; X 1 is N and X 2 is -C= or X 2 is N and X 1 is -C=; Y 3 is CR 3 or N; Y 6 is CR 6 or N; Y 8 is CR 8 or N; Y 9 is CR 9 or N; 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 , -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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 4 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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 optionally is selected from the group consisting of one or more R 4a may be substituted with; Each R 4a are 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same carbon 4a together to form oxo; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; W is -O-, -S-, or -NR 7 -is; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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; Each R bare independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C alkenyl, C-C 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, —NH, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C-C alkyl, or C-C haloalkyl; Each R c and R d are independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C alkenyl, C-C 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, —NH, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C-C alkyl, or C-C haloalkyl; 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, —NH, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C-C alkyl, or C-C haloalkyl.

[0022]

[0018] Also disclosed herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a pharmaceutically acceptable excipient.

[0023]

[0019] Also disclosed herein is a method for inhibiting the TYK2 enzyme in a patient or biological sample, comprising contacting the patient or biological sample with a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0024] Also disclosed herein are methods for 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 disorder, or a transplant-related disease. In some embodiments, the disease is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.

[0025] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference for the specific purposes identified herein. DETAILED DESCRIPTION OF THE INVENTION

[0026] Detailed Description of the Invention definition As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents, a reference to "the cell" includes a reference to one or more cells (or 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 properties such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be encompassed. The term "about" in connection with a number or numerical range means that the referenced number or numerical range is approximate within experimental variation (or within statistical experimental error), and thus the number or numerical range may, in some cases, vary by 1% to 15% of the stated number or numerical range. The term "comprising" (and related terms, e.g., "comprise" or "comprises" or "having" or "including") is not intended to exclude that in certain other embodiments, for example, that an embodiment of any composition of matter, composition, method, or process described herein "consists of" or "consists essentially of" the described features.

[0027] As used in this specification and the appended claims, the following terms have the meanings indicated below unless specified to the contrary.

[0028] "Oxo" means =O.

[0029] "Alkyl" means an optionally substituted straight-chain or optionally substituted branched-chain saturated hydrocarbon monovalent radical having 1 to about 10 carbon atoms, or 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, and the like. Wherever it appears herein, a numerical range such as "C1-C6 alkyl" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also includes the occurrence of the term "alkyl" without specifying a numerical range. In some embodiments, alkyl is C1-C6 alkyl. 10 alkyl, C1-C9 alkyl, C1-C8 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 stated herein, an alkyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkyl may be optionally substituted with oxo, halogen, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, an alkyl may be optionally substituted with oxo, halogen, —CN, —CF3, —OH, or —OMe. In some embodiments, an alkyl may be optionally substituted with halogen.

[0030] "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 from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The radical may be in either the cis or trans configuration about the double bond and 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-butadienyl, and the like. Whenever appearing herein, a numerical range such as "C2-C6 alkenyl" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also includes the occurrence of the term "alkenyl" where no numerical range is specified. In some embodiments, alkenyl refers to C2-C6 alkenyl. 10 alkenyl, C2-C9 alkenyl, C2-C8 alkenyl, C2-C7 alkenyl, C2-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl, or C2 alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkenyl can be optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl can be optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, an alkenyl can be optionally substituted with halogen.

[0031] "Alkynyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monovalent radical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever a numerical range such as "C2-C6 alkynyl" appears herein, it means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also includes the occurrence of the term "alkynyl" without a specified numerical range. In some embodiments, alkynyl refers to any C2-C6 alkynyl group. 10 alkynyl, C2-C9 alkynyl, C2-C8 alkynyl, C2-C7 alkynyl, C2-C6 alkynyl, C2-C5 alkynyl, C2-C4 alkynyl, C2-C3 alkynyl, or C2 alkynyl. Unless stated otherwise specifically in the specification, alkynyl groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkynyl can be optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl can be optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkynyl can be optionally substituted with halogen.

[0032]

[0028] "Alkylene" means a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkylene can be optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene can be optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, an alkylene can be optionally substituted with halogen.

[0033]

[0029] "Alkoxy" means a group of the formula -Oalkyl, where alkyl is as defined above. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy can be optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy can be optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, an alkoxy can be optionally substituted with halogen.

[0034] "Aminoalkyl" refers to an alkyl group, as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0035]

[0031] "Aryl" refers to a group derived from a hydrocarbon ring system containing hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring. Aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which can include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, an aryl is a 6- to 10-membered aryl. In some embodiments, an aryl is a 6-membered aryl. Aryl groups include, but are not limited to, aryl groups derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, an aryl is phenyl. Unless stated otherwise specifically in the specification, an aryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl can be optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, an aryl can be optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, an aryl can be optionally substituted with halogen.

[0036] "Cycloalkyl" means a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 15 carbon atoms, 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, or 3 to 4 carbon atoms (C3-C6, respectively). 15 Cycloalkyl, C3-C 10In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl or carbocycles include adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated in the specification, cycloalkyls can be 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.

[0037] "Deuteroalkyl" refers to an alkyl group, as defined above, substituted with one or more deuterium atoms. In some embodiments, the alkyl is substituted with one deuterium atom. In some embodiments, the alkyl is substituted with one, two, or three deuterium atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuterium atoms. Examples of deuteroalkyls include CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0038]

[0034] "Haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halogen atoms. In some embodiments, the alkyl is substituted with 1, 2, or 3 halogen atoms. In some embodiments, the alkyl is substituted with 1, 2, 3, 4, 5, or 6 halogen atoms. Haloalkyl includes, 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 is trifluoromethyl.

[0039] "Halo" or "halogen" means bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0040]

[0036] "Heteroalkyl" means an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl contains from 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof, and the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH3, -CHCH2OCH3, -CHCH2OCH2CH2OCH3, or -CH(CH3)OCH3. Unless stated otherwise specifically in the specification, a heteroalkyl may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroalkyl may be optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heteroalkyl may be optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a heteroalkyl may be optionally substituted with halogen.

[0041]

[0037] "Hydroxyalkyl" refers to an alkyl group, as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0042]

[0038] "Heterocycloalkyl" refers to a 3- to 24-membered, partially or fully saturated ring group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a heterocycloalkyl contains 1 or 2 heteroatoms selected from nitrogen and oxygen. Unless otherwise specifically stated herein, a heterocycloalkyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems; the nitrogen, carbon, or sulfur atoms in a heterocycloalkyl group can be optionally oxidized; and the nitrogen atom can be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having 2 to 15 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, or 2 to 4 carbon atoms (C2-C3, respectively). 15 Heterocycloalkyl, C2-C 10Heterocycloalkyl groups include, but are not limited to, heterocycloalkyl, C2-C8 heterocycloalkyl, C2-C6 heterocycloalkyl, C2-C5 heterocycloalkyl, or C2-C4 heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, cycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperaz ... Examples of heterocycloalkyl include thiazolidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes carbohydrates of all ring forms, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) constituting the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, heterocycloalkyls can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heterocycloalkyl is optionally substituted with halogen.

[0043]

[0039] "Heteroaryl" refers to a 5- to 14-membered ring system containing a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. A heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is attached through an aromatic ring atom) or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heteroaryl group can also be optionally oxidized; and the nitrogen atom can be optionally quaternized. In some embodiments, a heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, a heteroaryl is a 5- to 6-membered heteroaryl.Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, Examples include indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroaryl may be optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heteroaryl may be optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe.In some embodiments, the heteroaryl may be optionally substituted with halogen.

[0044] The terms "treat," "prevent," "ameliorate," and "inhibit," as well as derivatives thereof, as used herein, do not necessarily mean 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are various degrees of treatment, prevention, amelioration, and inhibition that one of skill in the art will recognize as having some potential benefit or therapeutic effect. In this regard, the disclosed methods can provide any amount or level of treatment, prevention, amelioration, or inhibition of a disease in a mammal. For example, a disease, including its symptoms or condition, can be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. It should be noted that the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disease, e.g., cancer or inflammatory disease. Also, for purposes of this invention, "treating," "preventing," "ameliorating," or "inhibiting" includes delaying the onset of the disease, or its symptoms or conditions.

[0045] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient quantity of a compound disclosed herein being administered to relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or inflammatory disease. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the quantity of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in a disease symptom. In some embodiments, an "effective" amount appropriate for a particular case is determined using techniques such as a dose escalation study.

[0046] As used herein, the term "TYK2-mediated" disorder, disease, and / or condition, as used herein, means 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 the severity of 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 disorders, and transplant-related diseases.

[0047] compound

[0043] 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 disorder, or a transplant-related disease. In some embodiments, the TYK2-mediated disease is cancer.

[0048] Disclosed herein are compounds of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0049] [ka]

[0050] During the ceremony: L is C1-C4 alkylene; wherein one or two carbon atoms may optionally be replaced by a heteroatom selected from oxygen, sulfur, nitrogen, or phosphate; L optionally comprises one or more R L may be substituted with; Each R L are independently deuterium, halogen, -CN, -OR b , -NO2, -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR cR d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same carbon L taken together form oxo, cycloalkyl, or heterocycloalkyl; Ring A is heteroaryl and Ring B is cycloalkyl or heterocycloalkyl; Or ring A is aryl or heteroaryl and ring B is heterocycloalkyl or 5-8 membered cycloalkyl; Each R A are 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 deuteroalkyl, 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 independently and optionally is selected from the group consisting of one or more R A1 may be substituted with; Each R A1 are 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same carbon A1 together to form oxo; n is 0-4; Each R B are 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 deuteroalkyl, 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 independently and optionally is selected from the group consisting of one or more R B1 May be replaced by; or two R on the same carbon B together to form oxo; Each R B1 are 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)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-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same carbon B1 together to form oxo; m is 0-4;

[0051] [ka]

[0052] is a single or double bond; X 1 is N and X 2 is -C= or X 2 is N and X 1 is -C=; Y 3 is CR 3 or N; Y 6 is CR 6 or N; Y 8 is CR 8 or N; Y 9 is CR 9 or N; 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 , -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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 4 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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 optionally is selected from the group consisting of one or more R 4a may be substituted with; Each R 4a are 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same carbon 4a together to form oxo; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; W is -O-, -S-, or -NR 7 -is; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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; Each R bare independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C alkenyl, C-C 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, —NH, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C-C alkyl, or C-C haloalkyl; Each R c and R d are independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C alkenyl, C-C 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, —NH, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C-C alkyl, or C-C haloalkyl; 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, —NH, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C-C alkyl, or C-C haloalkyl.

[0053] In some embodiments, the compound of Formula (I) is of Formula (Ia): or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0054] [ka]

[0055] In some embodiments, the compound of Formula (I) is of Formula (Ib), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0056] [ka]

[0057] In some embodiments, the compound of Formula (I) is of Formula (Ic), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0058] [ka]

[0059] In some embodiments, the compound of Formula (I) is of Formula (Id), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0060] [ka]

[0061] In some embodiments, the compound of Formula (I) is of Formula (Ie), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0062] [ka]

[0063] In some embodiments, the compound of formula (I) is of formula (If), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0064] [ka]

[0065] In some embodiments, the compound of Formula (I) is of Formula (Ig), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0066] [ka]

[0067] In some embodiments, the compound of Formula (I) is of Formula (Ih), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0068] [ka]

[0069] In some embodiments, the compound of Formula (I) is of Formula (Ii), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0070] [ka]

[0071] In some embodiments, the compound of Formula (I) is of Formula (Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0072] [ka]

[0073] In some embodiments, the compound of Formula (I) is of Formula (Ik) or Formula (Il), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0074] [ka]

[0075] wherein at least each R is independently H or D and at least one R is D.

[0076] In some embodiments, the compound of Formula (I) is of Formula (Im) or Formula (In), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0077] [ka]

[0078] wherein at least each R is independently H or D and at least one R is D.

[0079] In some embodiments, the compound of Formula (I) is of Formula (Io) or Formula (Ip), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0080] [ka]

[0081] wherein at least each R is independently H or D and at least one R is D.

[0082] In some embodiments, the compound of Formula (I) is of Formula (Iq) or Formula (Ir), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0083] [ka]

[0084] wherein at least each R is independently H or D and at least one R is D.

[0085] In some embodiments, the compound of Formula (I) is of Formula (Is) or Formula (It), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0086] [ka]

[0087] wherein at least each R is independently H or D and at least one R is D.

[0088]

[0060] In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or pharmaceutically acceptable salts, stereoisomers, or solvates thereof, ring A is heteroaryl and ring B is cycloalkyl or heterocycloalkyl.

[0089]

[0061] In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or pharmaceutically acceptable salts, stereoisomers, or solvates thereof, ring A is aryl or heteroaryl and ring B is heterocycloalkyl.

[0090]

[0062] In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or pharmaceutically acceptable salts, stereoisomers, or solvates thereof, ring A is aryl or heteroaryl and ring B is 5-8 membered cycloalkyl.

[0091] In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Ring B is a 5-6 membered cycloalkyl.

[0092] In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Ring B is a 5-membered cycloalkyl.

[0093] In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Ring B is a 5-6 membered heterocycloalkyl.

[0094] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring B is a 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring B is tetrahydrofuran or pyrrolidine. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring B is tetrahydrofuran.

[0095] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring A is a bicyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring A is indolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzothiophenyl, benzothiazolyl, benzofuranyl, or benzoxazolyl.

[0096] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring A is monocyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring A is pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl.

[0097] In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring A is phenyl.

[0098] In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or pharmaceutically acceptable salts, stereoisomers, or solvates thereof, Y 9 is N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Y 9 is CR 9 In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 9 are 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 deuteroalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 9is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 9 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 9 is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 9 is hydrogen.

[0099] In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or pharmaceutically acceptable salts, stereoisomers, or solvates thereof, Y 6 is N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Y 6 is CR 6 In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 6 are 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 deuteroalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 6is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 6 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 6 is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 6 is hydrogen.

[0100] In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or pharmaceutically acceptable salts, stereoisomers, or solvates thereof, Y 3 is N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Y 3 is CR 3 In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 3 are 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 deuteroalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 3is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 3 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 3 is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 3 is hydrogen.

[0101] In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or pharmaceutically acceptable salts, stereoisomers, or solvates thereof, Y 8 is N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Y 8 is CR 8 In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 8 are 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 deuteroalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 8is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 8 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 8 is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 8 is hydrogen.

[0102] In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or pharmaceutically acceptable salts, stereoisomers, or solvates thereof, R 4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 4 is C1-C6 alkyl or C1-C6 deuteroalkyl.

[0103] In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or pharmaceutically acceptable salts, stereoisomers, or solvates thereof, R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl.

[0104] In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or pharmaceutically acceptable salts, stereoisomers, or solvates thereof, R 5is C1-C6 alkyl or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 5 is hydrogen.

[0105] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, W is -S-. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, W is -O-.

[0106] In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, W is -NR 7 In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 7 is hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 7 is hydrogen. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 7 is C1-C6 alkyl.

[0107] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R A are independently deuterium, halogen, -CN, -OR b , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c Rd , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently and optionally is selected from the group consisting of one or more R A1 In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R A is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently and optionally is selected from the group consisting of one or more R A1 In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R A is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, aryl, or heteroaryl; wherein each alkyl, aryl, and heteroaryl independently and optionally is selected from the group consisting of one or more R A1 In some embodiments of a compound of Formula (I) or (Ia)-(Ij), 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 deuteroalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R Ais independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R A are independently C1-C6 deuteroalkyl.

[0108] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R A1 are 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R A1 are 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 deuteroalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R A1is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R A1 are independently deuterium, halogen, or C1-C6 alkyl.

[0109] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 0-2. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 0. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 1. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 2. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 3.

[0110] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R B are independently deuterium, halogen, -CN, -OR b , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NRc R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently and optionally is selected from the group consisting of one or more R B1 In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R B is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently and optionally is selected from the group consisting of one or more R B1 In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R B is independently deuterium, halogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, aryl, or heteroaryl; wherein each alkyl, aryl, and heteroaryl independently and optionally is selected from the group consisting of one or more R B1 In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R B is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R Bis independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R B are independently C1-C6 alkyl.

[0111] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R B1 are 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R B1 are 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 deuteroalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R B1is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R B1 are independently deuterium, halogen, or C1-C6 alkyl.

[0112] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 0-2. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 0. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 1. In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 2. In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 3.

[0113] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C4 alkylene; wherein one carbon atom may optionally be replaced by a heteroatom selected from oxygen, sulfur, or nitrogen; and L optionally contains one or more R LIn some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C4 alkylene; wherein one carbon atom may optionally be replaced by a heteroatom selected from oxygen or sulfur; and L may optionally be substituted with one or more R L In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C4 alkylene; wherein one carbon atom is optionally replaced by oxygen; and L is optionally substituted with one or more R L In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C4 alkylene; wherein one carbon atom is replaced by a heteroatom selected from oxygen, sulfur, or nitrogen; and L optionally contains one or more R L In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C4 alkylene; wherein one carbon atom is replaced by a heteroatom selected from oxygen or sulfur; and L optionally contains one or more R L may be substituted with

[0114] In some embodiments of the compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C4 alkylene; wherein one carbon atom is replaced by oxygen; and L optionally contains one or more R L may be substituted with

[0115] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C3 alkylene; wherein one carbon atom may optionally be replaced by a heteroatom selected from oxygen, sulfur, or nitrogen; and L optionally contains one or more R L In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C3 alkylene; wherein one carbon atom may optionally be replaced by a heteroatom selected from oxygen or sulfur; and L may optionally be substituted with one or more R L In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C3 alkylene; wherein one carbon atom may optionally be replaced by an oxygen atom; and L may optionally be substituted with one or more R L In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C3 alkylene; wherein one carbon atom is replaced by a heteroatom selected from oxygen, sulfur, or nitrogen; and L optionally contains one or more R L In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C3 alkylene; wherein one carbon atom is replaced by a heteroatom selected from oxygen or sulfur; and L optionally contains one or more R L In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-C3 alkylene; wherein one carbon atom may optionally be replaced by an oxygen atom; and L may optionally be substituted with one or more R L may be substituted with

[0116] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C3-alkylene; wherein one carbon atom may optionally be replaced by a heteroatom selected from oxygen, sulfur, or nitrogen; and L optionally contains one or more R L In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C3-alkylene; wherein one carbon atom may optionally be replaced by a heteroatom selected from oxygen or sulfur; and L may optionally be substituted with one or more R L In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C3-alkylene; wherein one carbon atom may optionally be replaced by an oxygen atom; and L may optionally be substituted with one or more R L In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C3-alkylene; wherein one carbon atom is replaced by a heteroatom selected from oxygen, sulfur, or nitrogen; and L optionally contains one or more R L In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C3-alkylene; wherein one carbon atom is replaced by a heteroatom selected from oxygen or sulfur; and L optionally contains one or more R L In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C3-alkylene; wherein one carbon atom is replaced by an oxygen atom; and L optionally contains one or more R L may be substituted with

[0117] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-alkylene; wherein one carbon atom may optionally be replaced by a heteroatom selected from oxygen, sulfur, or nitrogen; and L optionally contains one or more R L In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-alkylene; wherein one carbon atom may optionally be replaced by a heteroatom selected from oxygen or sulfur; and L may optionally be substituted with one or more R L In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-alkylene; wherein one carbon atom may optionally be replaced by an oxygen atom; and L may optionally be substituted with one or more R L In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-alkylene; wherein one carbon atom is replaced by a heteroatom selected from oxygen, sulfur, or nitrogen; and L optionally contains one or more R L In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-alkylene; wherein one carbon atom is replaced by a heteroatom selected from oxygen or sulfur; and L optionally contains one or more R L In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C2-alkylene; wherein one carbon atom is replaced by an oxygen atom; and L optionally contains one or more R L may be substituted with

[0118] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R L are independently deuterium, halogen, -CN, -OR b , -NR c R d , -C(=O)R a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; or two R on the same carbon L and R are taken together to form oxo, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R L are independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; or two R on the same carbon L and R are taken together to form oxo, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R L are independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl.

[0119] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), 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 (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is -CH2-O- or -O-CH2-.

[0120] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R a is independently C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C-C alkyl, or C-C haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compounds described above, each R a are independently C1-C6 alkyl.

[0121] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R b is independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C-C alkyl, or C-C haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compounds described above, each R bis independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds described above, each R b is hydrogen. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R b are independently C1-C6 alkyl.

[0122] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R c and R d is independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C-C alkyl, or C-C haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R c and R d is independently hydrogen, C-C alkyl, C-C haloalkyl, or C-C deuteroalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R c and R d is independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds described above, each R c and R d In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R c and R d are independently C1-C6 alkyl.

[0123] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), 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 In some embodiments of a compound of Formula (I) or (Ia)-(Ij), 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 In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each of L, R A , R B , R 4 , R a , R b , R c , and R d In some embodiments of a compound of Formula (I) or (Ia)-(Ij), 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 with one substituent as defined herein.

[0124] In some embodiments of a compound of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, the compound is

[0125] [ka]

[0126] [ka]

[0127] [ka]

[0128] [ka]

[0129] [ka]

[0130] or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0131] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers and their corresponding mixtures. In some circumstances, the compounds described herein possess one or more chiral centers, with each center existing in either the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms and their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, mixtures, combinations, or interconversions of enantiomers and / or diastereomers resulting from a single preparation step are useful for the uses described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, separable complexes are preferred. In some embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomers are then recovered with the resolving agent.

[0132] labeled compound 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 pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are the same as those described herein except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds described herein, or solvates, or stereoisomers thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, e.g., 2 H, 3 H, 13 C. 14 C. l5 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Cl. Compounds described herein that contain the aforementioned isotopes and / or other isotopes of other atoms, and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are within the scope of this disclosure. Certain isotopically labeled compounds, e.g., 3 H and 14 Incorporation of radioactive isotopes such as C is useful for drug and / or substrate tissue distribution assays. Tritiated, i.e. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred due to their ease of preparation and detectability. 2Substitution with heavy isotopes such as H may confer several therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method.

[0133]

[0099] In some embodiments, the compounds described herein are labeled by other means, such as, but not limited to, the use of a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0134] pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating 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.

[0135] In some embodiments, the compounds described herein possess acidic or basic groups and thus react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the purified compound in its free form with the appropriate acid or base and isolating the salt thus formed.

[0136]

[0102] Examples of pharmaceutically acceptable salts include salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, and butyrate. Butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate , methanesulfonate, methoxybenzoate, methylbenzoate, hydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pyruvate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undeconate, and xylenesulfonate.

[0137] Additionally, the compounds described herein can be prepared by dissolving the free base form of the compounds in a pharmaceutically acceptable inorganic or organic acid, for example, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; as well as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanol, and the like. The compounds can be prepared as pharmaceutically acceptable salts formed by reaction with organic acids such as benzenesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfonic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0138] In some embodiments, compounds described herein containing free acid groups are reacted with a suitable base, such as a hydroxide, carbonate, bicarbonate, or sulfate salt 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, and aluminum salts. Illustrative bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl)4, etc.

[0139] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. The compounds described herein should be understood to also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

[0140] solvate 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 further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0141]

[0107] Solvates contain stoichiometric or non-stoichiometric amounts of a solvent, such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided by the present invention can exist in unsolvated as well as solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided by the present invention.

[0142] tautomers In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers falling within the formulas described herein. Tautomers are compounds that can interconvert by migration of a hydrogen atom accompanied by the exchange of a single bond and an adjacent double bond. At bonding configurations where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0143] Preparation of compoundsThe compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or from compounds described in the chemical literature."Commercially available chemicals" are those obtained from standard commercial sources, e.g., Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, e.g., 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. (Hauppauge, 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. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0144]

[0110] Suitable reference books and articles detailing the synthesis of reactants useful in the preparation of the compounds described herein, or referring to articles describing the preparation, 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. Additional suitable reference books and articles detailing the synthesis of, or referencing articles describing the preparation of, reactants useful in the preparation of the compounds described herein 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, RV, "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC,「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;および「Chemistry of Functional Groups」John Wiley & Sons、in 73 volumesがある。.

[0145]

[0111] Specific and similar reactants are optionally identified through indexes of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, available in most public and university libraries, as well as online. Chemicals that are known but not commercially available in catalogs may optionally be prepared by custom chemical synthesis companies, and many standard chemical supply companies (see, for example, the list above) offer custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is PH Stahl & CG Wermuth, "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.

[0146] Pharmaceutical Composition In certain embodiments, the compounds described herein are administered as pure chemicals. In some embodiments, the compounds described herein are administered as pure chemicals, e.g., as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st The compound is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the chosen route of administration and standard pharmaceutical practice, as described in (Ed. Mack Pub. Co., Easton, PA (2005)).

[0147]

[0113] Thus, the present invention provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0148]

[0114] In certain embodiments, the compounds provided by the present invention 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, such as, for example, unreacted intermediates or synthetic by-products produced in one or more steps of the synthetic method.

[0149]

[0115] Pharmaceutical compositions are administered in a manner appropriate to the disease being treated (or prevented). The appropriate dose and the appropriate duration and frequency of administration are 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. In general, an appropriate dose and treatment regimen provides a sufficient amount of the composition to provide a therapeutic and / or prophylactic benefit (e.g., improved clinical outcome such as faster complete or partial remission, or longer disease-free and / or overall survival, or reduced severity of symptoms). Optimal doses are generally determined using experimental models and / or clinical trials. Optimal doses depend on the patient's body mass, weight, or blood volume.

[0150] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, pulmonary, intradermal, intrathecal, 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, intranasal administration, topical administration, or intraocular 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, lotion, eye drop, or ear drop. In some embodiments, the pharmaceutical composition is formulated as a tablet.

[0151] Appropriate doses and dosing regimens are determined by traditional range-finding techniques known to those skilled in the art. Generally, treatment is initiated with smaller doses that are less than the optimal dose of the compounds disclosed herein. Thereafter, the dose is increased by small increments until the optimum effect under the circumstances is reached. In some embodiments, the method involves administering from about 0.1 μg to about 50 mg of at least one compound described herein per kg of subject body weight. For a 70 kg patient, a dose of from about 10 μg to about 200 mg of the compounds disclosed herein would more commonly be used, depending on the subject's physiological response.

[0152] By way of example only, the dose of a compound described herein for the methods of treating a disease described herein is from about 0.001 to about 1 mg per kg of subject body weight per day, e.g., 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 per kg of body weight per day. In some embodiments, the dose of a compound described herein for the described methods is about 1 to about 1000 mg per kg of body weight of the subject being treated per day, e.g., 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.

[0153] Treatment method The compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are useful for inhibiting the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by the compounds and methods is TYK2.

[0154]

[0120] The present invention provides compounds that are inhibitors of TYK2 and are therefore useful in treating one or more disorders associated with the activity of TYK2 or mutants thereof.

[0155]

[0121] The present invention provides a method for 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 disorder, or a transplant-related disease, said 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.

[0156] In some embodiments, the disease or disorder is an autoimmune disease, hi some embodiments, the disease or disorder is selected from type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behcet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0157] In some embodiments, the disease or disorder is an inflammatory disease, hi some embodiments, the inflammatory disease is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, or inflammatory bowel disease.

[0158] 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, myelofibrosis, essential thrombocytosis, or thrombocytosis.

[0159] In some embodiments, the disease or disorder is an endocrine disease. In some embodiments, the endocrine disease is polycystic ovary syndrome, Crouzon syndrome, or type 1 diabetes.

[0160] In some embodiments, the disease or disorder is a neurological disorder, hi some embodiments, the neurological disorder is Alzheimer's disease.

[0161] In some embodiments, the proliferative disorder 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.

[0162] In some embodiments, the disease or disorder is transplant-related. In some embodiments, the transplant-related disease or disorder is transplant rejection or graft-versus-host disease.

[0163] 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 disorder is associated with IL-12 signaling. In some embodiments, the disease or disorder is associated with IL-23 signaling.

[0164]

[0130] The present invention provides a method for treating inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0165] The present invention provides methods of treating other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, diseases and conditions of the eye such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose, such as allergic rhinitis, and inflammatory diseases involving an autoimmune response or having an autoimmune component or etiology, for example, autoimmune blood diseases (e.g., hemolytic anemia, aplastic anemia, vera anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, Autoimmune inflammatory bowel diseases (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cholangitis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal conjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic fever syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. idiopathic nephrotic syndrome or minimal change nephritis)nephropathy), chronic granulomatous disease, endometriosis, leptospirosis kidney disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic, mild, moderate, severe, bronchitis, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, ocular allergies, silica-induced disease, COPD (injury, airway inflammation, bronchial hyperresponsiveness, remodeling or reduction of disease progression), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, myositis associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervix inflammation, 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-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis For the treatment of myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0166]

[0132] In some embodiments, the inflammatory disease is acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndromes (CAPS), or osteoarthritis.

[0167] In some embodiments, the inflammatory disease is a Th1 or Th17 mediated disease. In some embodiments, the Th17 mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0168] In some embodiments, the inflammatory disease is Sjogren's syndrome, an allergic disease, osteoarthritis, an eye condition such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, or a disease affecting the nose such as allergic rhinitis.

[0169] Combination therapy

[0135] Optionally, the compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are administered in combination with a second therapeutic agent.

[0170]

[0136] In some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein in conjunction with a second therapeutic agent (including a therapeutic regimen) that also has a therapeutic benefit.

[0171] In one 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, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0172] In either case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient is simply the additive of the two therapeutic agents, or the patient experiences a synergistic benefit.

[0173] In certain embodiments, when a compound disclosed herein is administered in combination with a second therapeutic agent, different therapeutically effective doses of the compound disclosed herein are utilized in the formulation of pharmaceutical compositions and / or treatment regimens. The therapeutically effective doses of the agents and other agents used in the combination treatment regimen may optionally be determined by means similar to those described herein above for the active agents themselves. The prophylactic / treatment methods described herein also encompass the use of metronomic dosing, i.e., providing more frequent, lower doses to minimize toxic side effects. In some embodiments, the combination treatment regimen includes a treatment regimen in which administration of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is initiated before, during, or after treatment with a second agent described herein, and continues during or any time after treatment with the second agent has ended. Also encompassed are treatments in which a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a second agent used in combination are administered simultaneously or at different times and / or at decreasing or increasing intervals during the treatment period. Combination treatment also includes cyclical treatments that are started and stopped at different times to aid in the clinical management of the patient.

[0174] It is understood that the dosage regimen to treat, prevent, or ameliorate the condition for which relief is sought will vary according to a variety of factors (e.g., the disease, disorder, or condition from which the subject suffers; the age, weight, sex, diet, and health of the subject). Thus, in some cases, the dosage regimen actually employed will vary and, in some embodiments, will deviate from the dosage regimens set forth herein.

[0175] For the combination therapies described herein, the dose of the co-administered compound will vary depending on the type of co-agent used, the particular agent used, the disease or condition being treated, etc. In additional embodiments, when co-administered with a second therapeutic agent, the compounds provided by the present invention are administered simultaneously with or sequentially with the second therapeutic agent.

[0176] In combination therapy, multiple therapeutic agents (one of which is a compound described herein) are administered in any order, or even simultaneously. If administration is simultaneous, the multiple therapeutic agents may be provided in a single, combined form, or in multiple forms (e.g., as a single pill or as two separate pills), by way of example only.

[0177] The compounds described herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, and combination therapies, may be administered before, during, or after the onset of a disease or condition, and the timing of administering compositions containing the compounds may vary. Thus, in one embodiment, the compounds described herein are used as prophylactics and are administered continuously to subjects prone to developing a condition or disease to prevent the onset of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during the onset of symptoms or as soon as possible after the onset of symptoms. In certain embodiments, the compounds described herein are administered as soon as practicable after the onset of a disease or condition is detected or suspected, for the time required to treat the disease. In some embodiments, the length of treatment required may vary, and the length of treatment may be adjusted to suit the specific needs of each subject. For example, in certain embodiments, the compounds described herein, or compositions containing the compounds, are administered for at least two weeks, from about one month to about five years.

[0178] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are administered in combination with an adjuvant. In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by the administration of an adjuvant (i.e., an adjuvant that has minimal therapeutic benefit by itself, but when combined with another therapeutic agent, enhances the overall therapeutic benefit to the patient). [Example]

[0179] Intermediate 1

[0180] [ka]

[0181] Step 1: Intermediate 1b To a solution of intermediate 1a (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 N2. After cooling to room temperature, the mixture was poured into 2 M aqueous NaOH solution (750 mL) at pH = 12 at 0 °C. DCM (800 mL) was added to the mixture, 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 silica gel flash column chromatography (petroleum ether / EtOAc = 2 / 1) to give the product intermediate 1b (49 g, 67% yield) as a yellow solid. LCMS [M+1] + =201.2.

[0182] Step 2: Intermediate 1c A solution of intermediate 1b (49 g, 243.8 mmol) in AcOH (530 mL) and H2O (100 mL) was cooled to 0°C, followed by the addition of NaNO2 (13.36 g, 193.6 mmol) in water (167 mL). The reaction mixture was stirred for 30 min at room temperature. Upon completion, the gradual formation of a yellow precipitate was observed. The solid was collected by filtration, washed with 65% AcOH in water, and concentrated to give the product intermediate 1c (40.7 g, 78% yield) as a yellow solid. LCMS [M+1] + =212.2.

[0183] Step 3: Intermediate 1d, Intermediate 1d', and Intermediate 1d" To a solution of intermediate 1c (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, and the filtrate was concentrated. The crude product was purified by silica gel flash column chromatography (petroleum ether / DCM = 1 / 1) to give the product intermediate 1d (800 mg, 24% yield, retention time: 1.48 min) as a white solid, intermediate 1d' (400 mg, 18% yield, retention time: 1.42 min) as a white solid, and intermediate 1d" (500 mg, 25% yield, retention time: 1.33 min) as a white solid. LCMS [M+1] + =229.2.

[0184] Step 4: Intermediate 1 To a solution of intermediate 1d (800 mg, 3.5 mmol) in CCl4 (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 silica gel flash column chromatography (petroleum ether / DCM = 1 / 1) to give the product intermediate 1 (700 mg, 65% yield) as a white solid. LCMS [M+1] + =306.2.

[0185] Example 1: General procedure for the synthesis of Example 1

[0186] [ka]

[0187] Step 1: Example 1b To a solution of Example 1a (5.0 g, 36.34 mmol) and Et3N (5.52 g, 54.50 mmol) in DCM (100 mL) was added Boc2O (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% to 5%) to give Example 1b (5.0 g, 68% yield) as a white solid. LCMS [M-Boc+1] + =102.1.

[0188] Step 2: Example 1d To a solution of Example 1b (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. H2O (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 give Example 1d (0.3 g, 92% yield) as a yellow oil. LCMS [M-2Boc+1] + =328.1.

[0189] Step 3: Example 1e 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 NHBoc (127 mg, 1.09 mmol). The reaction mixture was degassed with argon three 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, 47% yield) as a colorless oil. LCMS [M-Boc+1] + =265.2.

[0190] Step 4: Example 1f 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 vacuo. The pH of the residue was adjusted to 9 with 1 M NaHCO3. Then 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 vacuo. The residue, Example 1f (0.17 g, 100% yield), was obtained as a yellow oil, which was used in the next step without further purification. LCMS [M-Boc+1] + =265.2.

[0191] Step 5: Example 1h 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, 11% yield) as a colorless solid. LCMS [M+1] + =573.2.

[0192] Step 6: Example 1i To a solution of Example 1h (0.1 g, 0.17 mmol) in dioxane (1 mL) was added t-BuXphosPd G3 (28 mg, 0.035 mmol) and Cs2CO3 (171 mg, 0.52 mmol). The reaction mixture was degassed with argon three 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.

[0193] Step 7: Example 1 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 NaHCO3. Then the mixture was extracted with DCM (50 mL * 3). The combined organic layer was washed with 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) δ 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).

[0194] Example A. TYK2 JH2 Domain Binding Assay The binding constants for the JH2 domain of the compounds described herein were determined using the following protocol for the KINOMEscan® 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. Extracts were prepared from these HEK293 cells in M-PER extraction buffer (Pierce) according to the manufacturer's instructions in the presence of Protease Inhibitor Cocktail Complete (Roche) and Phosphatase Inhibitor Cocktail Set II (Merck). The TYK2 (JH2 domain pseudokinase) fusion protein was labeled with a chimeric double-stranded DNA tag containing the NFkB-binding site fused to the amplicon for qPCR readout, which was added directly to the expression extract (final concentration of the DNA-tag in the binding reaction was 0.1 nM).

[0195] Streptavidin-coated magnetic beads (Dynal M280) were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for binding assays. The ligand-treated beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and reduce nonspecific binding.

[0196] Binding reactions are assembled by combining 16 μl of DNA-tagged kinase extract, 3.8 μl of ligand-treated affinity beads, and 0.18 μl of test compound (PBS / 0.05% Tween 20 / 10 mM DTT / 0.1% BSA / 2 μg / ml sonicated salmon sperm DNA). Extracts are used directly in binding assays at a total stock dilution of ≥10,000 (final DNA-tagged enzyme concentration <0.1 nM) without an enzyme purification step. Extracts are DNA-tagged and diluted into binding reactions in a two-step process. First, extracts are diluted 1:100 with 1× 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 for 15 minutes at room temperature and then diluted 1:100 in 1x binding buffer. Test compounds were prepared as 111x 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 dispensed into 100% DMSO by acoustic transfer (contactless dispensing). Compounds were then diluted directly into the assay to a final DMSO concentration of 0.9%. All reactions were performed in a polypropylene 384-well plate. Each had a final volume of 0.02 mL. The assay was incubated for 1 hour at room temperature with shaking. The beads were then pelleted and washed with wash buffer (1x PBS, 0.05% Tween 20) to remove displaced kinase and test compound. The washed beads were resuspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated for 30 minutes at room temperature with shaking. The kinase concentration in the eluate was measured by qPCR. qPCR reactions were constructed by adding 2.5 μL of kinase eluate to 7.5 μL of qPCR master mix containing 0.15 μM amplicon primer and 0.15 μM amplicon probe. The qPCR protocol consisted of a 10-minute hot start at 95°C, followed by 35 cycles of 15 seconds at 95°C and 1 minute at 60°C.

[0197] Test compounds are prepared as 111x 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 are dispensed into 100% DMSO by acoustic transfer (non-contact dispensing). Compounds are then diluted directly into the assay so that the final DMSO concentration is 0.9%. Kd is determined using a top compound concentration of 30,000 nM. Kd measurements are performed in duplicate.

[0198] Binding constants (Kd) were calculated using the Hill equation for standard dose-response curves:

[0199]

number

[0200]

[0161] The Hill Slope was set to -1. The curves were fitted using nonlinear least-squares fitting 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)). The results are shown in Table 1.

[0201] [Table 1]

[0202] Example B: INFα-induced pSTAT5 in human PBMCs Fresh human PBMCs were resuspended in RPMI 1640 medium containing 10% FBS. Cells were seeded into round-bottom 96-well plates at a concentration of 200,000 cells / well. A 10-point dilution series of test compounds (highest dose 10 μM, 1:5 dilution) was added to the wells using a liquid dispenser (Tecan D300e) and incubated for 1 hour at 37°C. Human INFα 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 using the Phospho STAT5 (Tyr693) Kit (Meso Scale Discovery) according to the manufacturer's protocol.

[0203]

[0163] For calculation of inhibition rate, the relative pSTAT5 signal of each well = the pSTAT5 signal of each well - the mean pSTAT5 signal of the baseline.

[0204] % Inhibition = (mean pSTAT5 signal in INFα-treated wells - relative pSTAT5 signal in each compound-containing well) / mean pSTAT5 signal in INFα-treated wells * 100%.

[0205] Curves were plotted as % inhibition (y-axis) versus compound concentration (x-axis) and fitted with GraphPad Prism 7.0 as log(inhibitor) versus normalized response—variable slope. The control is BMS-986165:

[0206] [ka]

[0207]

[0166] The results are shown in Table 2.

[0208] [Table 2]

[0209] Example C: Pharmaceutical Composition Example C1: Parenteral Composition 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 administration by injection.

[0210] Example C2: Oral Composition 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, such as a hard gelatin capsule, suitable for oral administration.

[0211] Example C3: Sublingual (hard lozenge) composition To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, 100 mg of a compound described herein is mixed with 420 mg of powdered sugar, 1.6 mL of light corn syrup, 2.4 mL of distilled water, and 0.42 mL of mint extract. The mixture is gently blended and cast to form a lozenge suitable for buccal administration.

[0212]

[0170] The examples and embodiments described herein are merely illustrative, and in some embodiments, various modifications or variations are within the scope of the disclosure and the appended claims. Scope of claims at the time of international application [Section 1] A compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony: L is C1-C4 alkylene; wherein one or two carbon atoms may optionally be replaced by a heteroatom selected from oxygen, sulfur, nitrogen, or phosphate; L optionally comprises one or more R L may be substituted with; Each RL are 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same carbon L together form oxo, cycloalkyl, or heterocycloalkyl; Ring A is heteroaryl and Ring B is cycloalkyl or heterocycloalkyl; or ring A is aryl or heteroaryl and ring B is heterocycloalkyl or 5-8 membered cycloalkyl; Each R A are 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 deuteroalkyl, 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 independently and optionally is selected from the group consisting of one or more R A1 may be substituted with; Each R A1 are 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same carbon A1 together to form oxo; n is 0-4; Each R B are 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 deuteroalkyl, 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 independently and optionally is selected from the group consisting of one or more R B1 may be substituted with; or two R on the same carbon B together to form oxo; Each R B1 are 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)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-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same carbon B1 together to form oxo; m is 0-4; [ka] is a single or double bond; X 1 is N and X 2 is -C= or X 2 is N and X 1 is -C=; Y 3 is CR 3 or N; Y 6 is CR 6 or N; Y 8 is CR 8 or N; Y 9 is CR 9 or N; 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, -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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 4 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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 optionally is selected from the group consisting of one or more R 4a may be substituted with; Each R 4a are 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same carbon 4a together to form oxo; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; W is -O-, -S-, or -NR 7 - and; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; Each R a are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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; Each R bare independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C alkenyl, C-C 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, —NH, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C-C alkyl, or C-C haloalkyl; Each R c and R d are independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C alkenyl, C-C 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, —NH, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C-C alkyl, or C-C haloalkyl; 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, —NH, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C-C alkyl, or C-C haloalkyl. [Section 2] The compound of formula (I) has the formula (Ia): [ka] 2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, which is: [Section 3] The compound of formula (I) has formula (Ib): [ka] 2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, which is: [Section 4] The compound of formula (I) has the formula (Ic): [ka] 2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, which is: [Section 5] The compound of formula (I) has the formula (Id): [ka] 2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, which is: [Section 6] The compound of formula (I) has formula (Ie): [ka] 2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, which is: [Section 7] The compound of formula (I) has the formula (If): [ka] 2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, which is: [Section 8] The compound of formula (I) has the formula (Ig): [ka] 2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, which is: [Section 9] The compound of formula (I) has the formula (Ih): [ka] 2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, which is: [Section 10] The compound of formula (I) has the formula (Ii): [ka] 2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, which is: [Section 11] The compound of formula (I) has the formula (Ij): [ka] 2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, which is: [Section 12] 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein ring A is heteroaryl and ring B is cycloalkyl or heterocycloalkyl. [Section 13] 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein ring A is aryl or heteroaryl and ring B is heterocycloalkyl. [Section 14] 12. The compound according to any one of claims 1 to 11, wherein ring A is aryl or heteroaryl, and ring B is 5- to 8-membered cycloalkyl, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. [Section 15] 15. The compound according to claim 12 or 14, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein ring B is a 5- to 6-membered cycloalkyl. [Section 16] 16. The compound of claim 12, 14, or 15, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein Ring B is a 5-membered cycloalkyl. [Section 17] 14. The compound according to claim 12 or 13, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein ring B is a 5- to 6-membered heterocycloalkyl. [Section 18] 18. The compound of claim 12, 13, or 17, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein Ring B is a 5-membered heterocycloalkyl. [Section 19] 19. The compound according to any one of claims 12 to 18, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein ring A is a bicyclic heteroaryl. [Section 20] 20. The compound according to any one of claims 12 to 19, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein ring A is indolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzothiophenyl, benzothiazolyl, benzofuranyl, or benzoxazolyl. [Section 21] 19. The compound according to any one of claims 12 to 18, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein ring A is a monocyclic heteroaryl. [Section 22] 22. The compound according to any one of claims 12 to 18 and 21, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein ring A is pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl. [Section 23] 15. The compound of claim 13 or 14, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein ring A is phenyl. [Section 24] Y 9is N, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. [Section 25] Y 6 is CR 6 25. The compound according to any one of claims 1 to 24, wherein: [Section 26] R 6 26. The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein is hydrogen. [Section 27] Y 3 is CR 3 27. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein: [Section 28] R 3 28. The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein is hydrogen. [Section 29] Y 8 is N, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. [Section 30] Y 8 is CR 8 30. The compound according to any one of claims 1 to 29, wherein: [Section 31] R 8 31. The compound of any one of claims 1 to 28 and 30, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein is hydrogen. [Section 32] R 4 The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [Section 33] R4 33. The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein is C1-C6 alkyl or C1-C6 deuteroalkyl. [Section 34] R 5 34. The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein is hydrogen. [Section 35] 35. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein W is -O-. [Section 36] W is -NR 7 35. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein: [Section 37] R 7 37. The compound according to any one of claims 1 to 34 and 36, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein is hydrogen or C1-C6 alkyl. [Section 38] Each R A are 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently and optionally is selected from the group consisting of one or more R A1 38. The compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, optionally substituted with: [Section 39] Each R Aare independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently and optionally is selected from the group consisting of one or more R A1 39. The compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, optionally substituted with: [Section 40] Each R A are independently deuterium, halogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, aryl, or heteroaryl; wherein each alkyl, aryl, and heteroaryl independently optionally contains one or more R A1 39. The compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, optionally substituted with: [Section 41] Each R A are independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. [Section 42] Each R A are independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. [Section 43] Each R A are independently C1-C6 deuteroalkyl, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. [Section 44] 44. The compound according to any one of claims 1 to 43, wherein n is 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. [Section 45] 44. The compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein n is 1. [Section 46] L is C2-C4 alkylene; wherein one carbon atom may be optionally replaced by a heteroatom selected from oxygen, sulfur, or nitrogen; L is optionally one or more R L 46. ​​The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, optionally substituted with: [Section 47] L is C2-C3 alkylene; wherein one carbon atom may be optionally replaced by a heteroatom selected from oxygen, sulfur, or nitrogen; L is optionally one or more R L 46. ​​The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, optionally substituted with: [Section 48] L is C2-alkylene; wherein one carbon atom may optionally be replaced by a heteroatom selected from oxygen, sulfur, or nitrogen; L is optionally one or more R L 46. ​​The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, optionally substituted with: [Section 49] 49. The compound according to any one of claims 46 to 48, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein the heteroatom is oxygen or sulfur. [Section 50] 50. The compound according to any one of claims 46 to 49, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein the heteroatom is oxygen. [Section 51] 51. The compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein L is -CH2-O- or -O-CH2-. [Section 52] The compound [ka] [ka] [ka] [ka] [ka] 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, selected from: [Section 53] 53. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a pharmaceutically acceptable excipient. [Section 54] 53. A method of inhibiting the TYK2 enzyme in a patient or biological sample, comprising contacting the patient or biological sample with a compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. [Section 55] A method for treating a disease mediated by TYK2, comprising administering to a patient in need of treatment for the disease a compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. [Section 56] 56. The method of claim 55, wherein the TYK2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disorder, or a transplant-related disease. [Section 57] 56. The method of claim 55, wherein the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.

Claims

1. A compound of formula (Ik), or a pharmaceutically acceptable salt or stereoisomer thereof: 【Chemistry 1】 wherein each R is independently H or D.

2. The compound 【Chemistry 2】 10. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt or stereoisomer thereof.

3. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

4. 4. The pharmaceutical composition according to claim 3, for use in treating a disease mediated by TYK2, wherein the disease mediated by TYK2 is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disorder, or a transplant-related disease.

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