TYK2 INHIBITORS AND USES THEREOF

Abstract

Described herein are compounds useful for treating TYK2-mediated disorders.In some embodiments, the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 320,320, filed March 16, 2022, the contents of which are incorporated by reference in their entirety herein. [Background technology]

[0002]

[0002] 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 associates with the cytoplasmic domains of type I and type II cytokine receptors and interferon type I and III receptors and is activated by these receptors upon cytokine binding. Cytokines implicated 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 limitins) and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, L-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF). Activated TYK2 then proceeds to phosphorylate additional signaling proteins, such as STAT family members including STAT1, STAT2, STAT4, and STAT6.

[0003]

[0003] TYK2 activation by IL-23 has been associated with inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. A genome-wide association study of 2,622 individuals with psoriasis identified an association between disease susceptibility and TYK2. Knockout of TYK2 or inhibition of tyrphostins significantly reduced both IL-23-induced and IL-22-induced dermatitis.

[0004] 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.

[0005]

[0005] Reduction of TYK2 activity protects joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis. Mechanistically, reduction of TYK2 activity reduced production of Th1 / Th17-associated cytokines and matrix metalloproteinases, as well as other key markers of inflammation.

[0006]

[0006] TYK2 knockout mice exhibit complete resistance in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)) and lack CD4 T cell infiltration in the spinal cord compared to controls, suggesting that TYK2 is essential for the development of pathogenic CD4-mediated disease in MS. This confirms earlier studies linking increased TYK2 expression with MS susceptibility. Loss-of-function mutations in TYK2 result in reduced demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelinating disorders.

[0007] TYK2 is the only signaling messenger common to both IL-12 and IL-23. TYK2 knockout reduced methylated BSA injection-induced footpad thickness, imiquimod-induced psoriasis-like skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice.

[0008]

[0008] Joint linkage and association studies of various type I IFN signaling genes with systemic lupus erythematosus (SLE, an autoimmune disorder) have shown a strong, significant correlation between loss-of-function mutations in TYK2 and reduced prevalence of SLE in families with affected members. Genome-wide association studies comparing individuals with SLE with unaffected cohorts have shown a highly significant correlation between the TYK2 locus and SLE.

[0009] TYK2 has been shown to play an important role in maintaining tumor surveillance, and TYK2 knockout mice showed impaired cytotoxic T cell responses and accelerated tumor development. However, these effects were associated with efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors are highly suitable for the treatment of autoimmune disorders or graft rejection. Although other JAK family members, such as JAK3, have similar roles in the immune system, TYK2 has been suggested as a superior target because it is involved in fewer, more closely related signaling pathways and produces fewer off-target effects.

[0010]

[0010] Studies of T-cell acute lymphoblastic leukemia (T-ALL) suggest that T-ALL is critically dependent on IL-10 via STAT1-mediated signaling through TYK2 to maintain cancer cell survival via upregulation of the anti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, reduced cell growth. Specific activating mutations on TYK2 that promote cancer cell survival include activating mutations on the FERM domain (G36D, S47N, and R425H), JH2 domain (V731I), and kinase domain (E957D and R1027H). However, it was also identified that the kinase function of TYK2 is required for increased cancer cell viability. This was because TYK2 enzymes characterized by kinase-inactivating mutations (M978Y or M978F) in addition to activating mutations (E957D) resulted in failed conversion.

[0011]

[0011] Thus, selective inhibition of TYK2 has been proposed as a suitable target for patients with IL-10 and / or BCL2-dependent tumors, e.g., 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. Reduction of TYK2 phosphorylation of STAT3 following Aβ administration resulted in reduced neuronal cell death, and increased phosphorylation of STAT3 was observed in postmortem brains of Alzheimer's patients.

[0012]

[0012] Inhibition of the JAK-STAT signaling pathway has also been implicated in hair growth and reversal of hair loss associated with alopecia areata. Summary of the Invention [Problem to be solved by the invention]

[0013]

[0013] Thus, compounds that inhibit the activity of TYK2, particularly those with selectivity over JAK2, would be beneficial. Such compounds should deliver a pharmacological response that advantageously treats one or more of the conditions described herein without producing the side effects associated with inhibition of JAK2.

[0014]

[0014] There is therefore a need to provide novel inhibitors which have more potent or advantageous pharma- ceutical relevant properties, such as greater selectivity over other JAK kinases, particularly JAK2. [Means for solving the problem]

[0015]

[0015] Compounds useful for treating TYK2-mediated disorders are described herein. In some embodiments, the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. In some embodiments, the TYK2-mediated disorder is cancer.

[0016] For example, a compound of formula I:

[0017] [ka]

[0018] [In the formula, Ring A is a 6,5 ​​or 6,6 fused bicyclic heteroaryl containing 2, 3, or 4 ring nitrogens; R A are independently selected for each occurrence as hydrogen, halogen, -NR a R b , C 1~ C6 alkyl, and C 1~ C6 alkoxy; 1~ C6 alkyl and C 1~ The C6 alkoxy may be substituted with one or more halogens or deuterium. Ring B is a 6,5 ​​or 6,6 fused bicyclic heteroaryl containing 1, 2 or 3 ring nitrogens; R B are independently selected for each occurrence as hydrogen, halogen, -NR a R b , C 1~ C6 alkyl, and C 1~ C6 alkoxy; 1~ C6 alkyl and C 1~ The C6 alkoxy may be substituted with one or more halogens or deuterium. Y is O, N(R a ), S(O) w , CH2, and a bond; Z is N(R a ) and O; R 1 Each occurrence independently represents deuterium, halogen, hydroxyl, -NR a R b , Cyano, C. 1~ C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1~ C6 heteroalkyl, and C 1~ C alkoxy; R 4 may be substituted on available carbons with hydroxyl or one or more halogens; R 2 and R 3 are independently hydrogen, deuterium, and C 1~ C alkyl (optionally substituted with one or more halogens); or R 2 and R 3 may be bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl; R a and R b is independently selected for each occurrence from hydrogen and C 1~ C6 alkyl, 1~ The C6 alkyl may be substituted with one or more halogens or deuterium. m is 1 or 2; n is 0 or 1, p is 0, 1, 2, 3 or 4; and w is 0, 1, or 2, or a pharma- ceutically acceptable salt and / or stereoisomer thereof.

[0019]

[0017] Formula III:

[0020] [ka]

[0021] [In the formula, Q is N and T is C, or Q is C and T is N, Q and T are each members of an aromatic heterocyclic ring system; V is N(R V ), W is N and X is N, or V is N and W is N(R V ), where X is N, or V is N, W is N, and X is N(R X ) or V is N and W is C(R W ), and X is N(R X ) or V is N(R V ), and W is C(R W ), where X is N, or V is N(R V ), W is N, and X is C(R X ) or V is N and W is N(R W ), and C is C(R X ) or V is C(R V ), and W is N(R W ), where X is N, or V is C(R V ), W is N, and X is N(R X ) or V is N and W is C(R W ), and X is C(R X ) or V is C(R V ), and W is C(R W ), where X is N, or V is O, W is N, and X is N(R X ) or V is C(R V ), W is N and X is O; V, W and X are each members of an aromatic heterocyclic ring system; Y is O, N(R a ), S(O) w , CH2, and a bond; R V , R W and R X are each independently hydrogen and C 1~ C6 alkyl, 1~ Each C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, and hydroxyl; R 1 is hydrogen or C 1~ C6 alkyl, C 1~ The C6 alkyl may be substituted with one or more halogens or deuterium. R 2 and R 3 are independently hydrogen, deuterium, and C 1~ C alkyl (optionally substituted with one or more halogens); or R 2 and R 3 may be bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl; R 4 Each occurrence independently represents deuterium, halogen, hydroxyl, -NR a R b , Cyano, C. 1~ C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1~ C6 heteroalkyl, and C 1~ C alkoxy; R 4 may be substituted on available carbons with hydroxyl or one or more halogens; R 5 and R 6 are independently hydrogen, deuterium, and C 1~ C alkyl (optionally substituted with one or more halogens); or R 5 and R 6 may be bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl; R a and R b is independently selected for each occurrence from hydrogen and C 1~ C6 alkyl, 1~ The C6 alkyl may be substituted with one or more deuterium atoms; m is 1 or 2; n is 0 or 1, p is 0, 1, 2, 3 or 4; and w is 0, 1, or 2, or a pharma- ceutically acceptable salt and / or stereoisomer thereof.

[0022] Furthermore, the compound of formula IV:

[0023] [ka]

[0024] [In the formula, Q is N and T is C, or Q is C and T is N, Q and T are each members of an aromatic heterocyclic ring system; V is N(R V ), W is N and X is N, or V is N and W is N(RV ), where X is N, or V is N, W is N, and X is N(R X ) or V is N and W is C(R W ), and X is N(R X ) or V is N(R V ), and W is C(R W ), where X is N, or V is N(R V ), W is N, and X is C(R X ) or V is N and W is N(R W ), and C is C(R X ) or V is C(R V ), and W is N(R W ), where X is N, or V is C(R V ), W is N, and X is N(R X ) or V is N and W is C(R W ), and X is C(R X ) or V is C(R V ), and W is C(R W ), where X is N, or V is O, W is N, and X is N(R X ) or V is C(R V ), W is N and X is O; V, W and X are each members of an aromatic heterocyclic ring system; Y is O, N(R a ), S(O) w , CH2, and a bond; R V , R W and R X are each independently hydrogen and C 1~ C6 alkyl, 1~Each C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, and hydroxyl; R 1 is hydrogen or C 1~ C6 alkyl, C 1~ The C6 alkyl may be substituted with one or more deuterium atoms; R 2 and R 3 are independently hydrogen, deuterium, and C 1~ C alkyl (optionally substituted with one or more halogens); or R 2 and R 3 may be bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl; R 4 Each occurrence independently represents deuterium, halogen, hydroxyl, -NR a R b , Cyano, C. 1~ C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1~ C6 heteroalkyl, and C 1~ C alkoxy; R 4 may be substituted on available carbons with hydroxyl or one or more halogens; R a and R b is independently selected for each occurrence from hydrogen and C 1~ C alkyl (optionally substituted with one or more halogens); m is 1 or 2; p is 0, 1, 2, 3 or 4; and w is 0, 1, or 2, or a pharma- ceutically acceptable salt and / or stereoisomer thereof.

[0025]

[0019] Formula V:

[0026] [ka]

[0027] [In the formula, Q is N and T is C, or Q is C and T is N, Q and T are each members of an aromatic heterocyclic ring system; V is N(R V ), W is N and X is N, or V is N and W is N(R V ), where X is N, or V is N, W is N, and X is N(R X ) or V is N and W is C(R W ), and X is N(R X ) or V is N(R V ), and W is C(R W ), where X is N, or V is N(R V ), W is N, and X is C(R X ) or V is N and W is N(R W ), and C is C(R X ) or V is C(R V ), and W is N(R W ), where X is N, or V is C(R V ), W is N, and X is N(R X ) or V is N and W is C(R W ), and X is C(R X ) or V is C(R V ), and W is C(R W ), where X is N, or V is O, W is N, and X is N(R X ) or V is C(R V ), W is N and X is O; V, W and X are each members of an aromatic heterocyclic ring system; Z is N(R a ) and O; R V , R W and R X are each independently hydrogen and C 1~ C6 alkyl, 1~ Each C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, and hydroxyl; R 1 is hydrogen or C 1~ C6 alkyl, C 1~ The C6 alkyl may be substituted with one or more deuterium atoms; R 2 and R 3 are independently hydrogen, deuterium, and C 1~ C alkyl (optionally substituted with one or more halogens); or R 2 and R 3 may be bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl; R 4 Each occurrence independently represents deuterium, halogen, hydroxyl, -NR a R b , Cyano, C. 1~ C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1~ C6 heteroalkyl, and C 1~ C alkoxy; R 4 may be substituted on available carbons with hydroxyl or one or more halogens; R a and R b is independently selected for each occurrence from hydrogen and C 1~ C6 alkyl, 1~ The C6 alkyl may be substituted with one or more deuterium atoms; m is 1 or 2; and p is 0, 1, 2, 3 or 4, or a pharma- ceutically acceptable salt and / or stereoisomer thereof.

[0028]

[0020] Also disclosed herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof, and a pharma- ceutically acceptable excipient.

[0029]

[0021] 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 pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

[0030] Also disclosed herein is a method of treating a TYK2-mediated disorder, comprising administering to a patient in need of treatment a compound disclosed herein, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments, the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-associated disorder. In some embodiments, the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031]

[0023] The features and other details of the present disclosure will now be described more particularly. Before further description of the present disclosure, certain terms utilized in the specification, examples, and appended claims are collected here. These definitions should be read as understood by those skilled in the art in view of the remainder of the disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. definition

[0024] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to an "agent" includes a plurality of such agents, a reference to a "cell" includes a reference to one or more cells (or cells) and equivalents thereof known to those of skill 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 included. The term "about," when referring to a number or numerical range, means that the stated number or numerical range is an approximation within experimental variation (or statistical experimental error), such that the number or numerical range, in some cases, will vary between 1% and 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, any compositions of matter, compositions, methods, or processes described herein "consist" or "consist essentially of" the described features.

[0032] As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meanings indicated below.

[0026] "Oxo" refers to =O.

[0033] "Alkyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain saturated hydrocarbon monoradical 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, etc. Whenever alkyl is present herein, numerical ranges are used, e.g., "C 1~ "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 the definition of the present invention also covers the occurrence of the term "alkyl" when no numerical range is specified. In some embodiments, alkyl is 1~ C 10 Alkyl, C 1~ C9 alkyl, C 1~ C8 alkyl, C 1~ C7 alkyl, C 1~ C6 alkyl, C 1~ C5 alkyl, C 1~ C4 alkyl, C 1~ C3 alkyl, C 1~C2 alkyl, or C1 alkyl. Unless otherwise specifically stated in the specification, alkyl groups may be substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl may be substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkyl may be substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkyl may be substituted with halogen.

[0034] "Alkenyl" refers to an optionally substituted straight chain or optionally substituted branched chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans configuration about the double bond(s) and should be considered 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 alkenyl is present in this specification, it is understood to be in a numerical range, e.g., "C 2~ "C6 alkenyl" means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the definition of the present invention also covers the occurrence of the term "alkenyl" when no numerical range is specified. In some embodiments, alkenyl is 2~ C 10 Alkenyl, C 2~ C9 Alkenyl, C 2~ C8 Alkenyl, C 2~ C7 alkenyl, C 2~ C6 alkenyl, C 2~ C5 alkenyl, C 2~ C4 alkenyl, C 2~C3 alkenyl, or C2 alkenyl. Unless otherwise specifically stated in the specification, an alkenyl group may be substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkenyl may be substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl may be substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, an alkenyl may be substituted with halogen.

[0035] "Alkynyl" refers to an optionally substituted straight chain or an optionally substituted branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadinyl, and the like. Whenever alkynyl is present in this specification, it is not necessarily limited to a numerical range, e.g., "C 2~ "C6 alkynyl" means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, however, the definition of the present invention also covers the occurrence of the term "alkynyl" when no numerical range is specified. In some embodiments, alkynyl is 2~ C 10 Alkynyl, C 2~ C9 alkynyl, C 2~ C8 alkynyl, C 2~ C7 alkynyl, C 2~ C6 alkynyl, C 2~ C5 alkynyl, C 2~ C4 alkynyl, C 2~C3 alkynyl, or C2 alkynyl. Unless otherwise specifically stated in the specification, alkynyl groups may be substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkynyl may be substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl may be substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkynyl may be substituted with halogen.

[0036]

[0030] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specifically stated in the specification, an alkylene group may be substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene may be substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene may be substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, an alkylene may be substituted with halogen.

[0037]

[0031] "Alkoxy" refers to a group of formula -Oalkyl, where alkyl is as defined above. Unless otherwise specifically stated in the specification, an alkoxy group may be substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy may be substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy may be substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, an alkoxy may be substituted with halogen.

[0038]

[0032] "Aminoalkyl" refers to an alkyl group substituted with one or more amines, where the alkyl group is as defined above. 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.

[0039]

[0033] "Aryl" refers to a group derived from a hydrocarbon ring system containing hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring. The aryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl groups include, but are not limited to, aryl groups derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene hydrocarbon ring systems. In some embodiments, the aryl is phenyl. Unless otherwise specifically stated in the specification, an aryl may be substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl may be substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl may be substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, an aryl may be substituted with halogen.

[0040] "Cycloalkyl" refers to a partially or fully saturated, monocyclic, or polycyclic carbocycle, 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 (C 3~ C 15 Cycloalkyl), 3 to 10 carbon atoms (C 3~ C10 Cycloalkyl), 3 to 8 carbon atoms (C 3~ C8 cycloalkyl), 3 to 6 carbon atoms (C 3~ C6 cycloalkyl), 3 to 5 carbon atoms (C 3~ C5 cycloalkyl), or 3 to 4 carbon atoms (C 3~ C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3-6 membered cycloalkyl. In some embodiments, the cycloalkyl is a 5-6 membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, 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. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated in the specification, cycloalkyls may be 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, cycloalkyls may be substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, cycloalkyls may be substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, cycloalkyls may be substituted with halogen.

[0041]

[0035] "Deuteroalkyl" refers to an alkyl group substituted with one or more deuterium atoms, where alkyl is as defined above. 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. Deuteroalkyls include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0042]

[0036] "Haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, where the alkyl group is as defined above. 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 halogens. 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.

[0043]

[0037] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0044] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C 1~A C6 heteroalkyl, which is composed of 1-6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof, and which is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH, -CHCHOCH, -CHCHOCHCHOCH, or -CH(CH)OCH. Unless otherwise specifically stated in the specification, a heteroalkyl may be substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl may be substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyl is optionally substituted with halogen.

[0045]

[0039] "Hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyls, where the alkyl group is as defined above. 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.

[0046]

[0040] "Heterocycloalkyl" refers to a 3-24 membered partially or fully saturated ring group containing 2-23 carbon atoms and 1-8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur. In some embodiments, heterocycloalkyl contains 1 or 2 heteroatoms selected from nitrogen and oxygen. Unless otherwise specifically stated in the specification, heterocycloalkyl groups can be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which can include fused (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems, in which the nitrogen, carbon or sulfur atoms in the heterocycloalkyl group can be oxidized and the nitrogen atom can be quaternized. Representative heterocycloalkyl groups include, but are not limited to, groups containing 2-15 carbon atoms (C2-C4). 15 Heterocycloalkyl), 2 to 10 carbon atoms (C 2~ C 10 Heterocycloalkyl), 2 to 8 carbon atoms (C 2~ C8 heterocycloalkyl), 2 to 6 carbon atoms (C 2~ C6 heterocycloalkyl), 2 to 5 carbon atoms (C 2~ C5 heterocycloalkyl), or 2 to 4 carbon atoms (C 2~C4 heterocycloalkyl). In some embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkyl. In some embodiments, the cycloalkyl is a 5-6 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-piperidin ... Examples of heterocycloalkyl include aryl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, 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 all ring forms of carbohydrates, 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 (including heteroatoms) of atoms making up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl can 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 heterocycloalkyl can be optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, heterocycloalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heterocycloalkyls are optionally substituted with halogen.

[0047]

[0041] "Heteroaryl" refers to a group of 5-14 membered ring systems containing a hydrogen atom, 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. Heteroaryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, including fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems, in which the nitrogen, carbon or sulfur atoms in the heteroaryl group can be oxidized and the nitrogen atom can be quaternized. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a 5-6 membered heteroaryl.Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, 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, 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 otherwise specifically stated in the specification, heteroaryl may be substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl may be substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryl may be substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroaryl may be substituted with halogen.

[0048]

[0042] The terms "treat", "prevent", "ameliorate" and "inhibit", and words derived therefrom, as used herein, do not necessarily mean 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are different degrees of treatment, prevention, amelioration, and inhibition that one of skill in the art would recognize as potentially beneficial or having a therapeutic effect. In this regard, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of a disorder in a mammal. For example, a disorder, including its symptoms or conditions, can be reduced, for example, by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, 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 a disorder, e.g., cancer or inflammatory disease. For purposes of this specification, "treating," "preventing," "ameliorating," or "inhibiting" also includes delaying the onset of a disorder, or a symptom or condition thereof.

[0049]

[0043] The term "effective amount" or "therapeutically effective amount" as used herein refers to the administration of a sufficient amount of a compound disclosed herein to alleviate 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 the disease, or any other desired change in a biological system. For example, an "effective amount" for use in therapy is the amount of a composition comprising a compound disclosed herein required to produce a clinically significant reduction in a disease symptom. In some embodiments, the appropriate "effective" amount in any individual case is determined using techniques such as dose escalation studies.

[0050]

[0044] 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 disorders include, but are not limited to, autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and disorders associated with transplantation. compound

[0045] Compounds useful for treating TYK2-mediated disorders are described herein. In some embodiments, the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. In some embodiments, the TYK2-mediated disorder is cancer.

[0051] For example, a compound of formula I:

[0052] [ka]

[0053] [In the formula, Ring A is a 6,5 ​​or 6,6 fused bicyclic heteroaryl containing 2, 3, or 4 ring nitrogens; R A are independently selected for each occurrence as hydrogen, halogen, -NR a R b , C 1~ C6 alkyl, and C 1~ C6 alkoxy; 1~ C6 alkyl and C 1~ The C6 alkoxy may be substituted with one or more halogens or deuterium. Ring B is a 6,5 ​​or 6,6 fused bicyclic heteroaryl containing 1, 2 or 3 ring nitrogens; R Bare independently selected for each occurrence as hydrogen, halogen, -NR a R b , C 1~ C6 alkyl, and C 1~ C6 alkoxy; 1~ C6 alkyl and C 1~ C6 alkoxy may be substituted with one or more halogens or deuterium; Y is O, N(R a ), S(O) w , CH2, and a bond; Z is N(R a ) and O; R 1 Each occurrence independently represents deuterium, halogen, hydroxyl, -NR a R b , Cyano, C. 1~ C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1~ C6 heteroalkyl, and C 1~ C alkoxy; R 4 may be substituted on available carbons with hydroxyl or one or more halogens; R 2 and R 3 are independently hydrogen, deuterium, and C 1~ C alkyl (optionally substituted with one or more halogens); or R 2 and R 3 may be bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl; R a and R b is independently selected for each occurrence from hydrogen and C 1~ C6 alkyl, 1~ The C6 alkyl may be substituted with one or more halogens or deuterium. m is 1 or 2; n is 0 or 1, p is 0, 1, 2, 3 or 4; and w is 0, 1, or 2, or a pharma- ceutically acceptable salt and / or stereoisomer thereof.

[0054] In some embodiments, ring A is

[0055] [ka]

[0056] [In the formula, Q is N and T is C, or Q is C and T is N, R A is selected from the group consisting of -N(H)CH3, -NH2, hydrogen, and -OCH3; * represents the point of attachment to the -NH- group in formula I.

[0057] For example, in certain embodiments, ring A is

[0058] [ka]

[0059] is selected from the group consisting of: In another embodiment, ring A is

[0060] [ka]

[0061] [In the formula, T is N or CH; R A1 is selected from the group consisting of -N(H)CH3, -NH2, hydrogen, and -OCH3; R A2 is selected from the group consisting of hydrogen and -CH3; * represents the point of attachment to the -NH- group in formula I.

[0062] For example, in certain embodiments, ring A is

[0063] [ka]

[0064] is selected from the group consisting of: In a further embodiment, Ring B is

[0065] [ka]

[0066] [In the formula, V is N(R V ), W is N and X is N, or V is N and W is N(R V ), where X is N, or V is N, W is N, and X is N(R X ) or V is N and W is C(R W ), and X is N(R X ) or V is N(R V ), and W is C(R W ), where X is N, or V is N(R V ), W is N, and X is C(R X ) or V is N and W is N(R W ), and C is C(R X ) or V is C(R V ), and W is N(R W ), where X is N, or V is C(R V ), W is N, and X is N(R X ) or V is N and W is C(R W ), and X is C(R X ) or V is C(R V ), and W is C(R W ), where X is N, or V is O, W is N, and X is N(R X ) or V is C(R V ), W is N and X is O; or V is O and W is C(R W ), where X is N, or V is N and W is C(R W ), X is O, R V , R W and R X are each independently hydrogen and C 1~ C6 alkyl, 1~ Each C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, and hydroxyl; * represents the point of attachment to the -NH- group in formula I.

[0067] For example, in certain embodiments, ring B is

[0068] [ka]

[0069] [In the formula, R V , R W and R X are each independently selected from the group consisting of hydrogen, -CH3, and -CD3. In another embodiment, B is

[0070] [ka]

[0071] [In the formula, R V , R W and R X are each independently selected from the group consisting of hydrogen, -CH3, and -CD3. In still further embodiments, Ring B is

[0072] [ka]

[0073] [In the formula, U, V, W, X, Y, and Z are each independently N and C(R B ), where one or two of U, V, W, X, Y, and Z are N; R B Each occurrence independently represents hydrogen, halogen, or C. 1~ C3 alkyl, and C 1~ C alkoxy; * represents the point of attachment to the -NH- group in formula I.

[0074] For example, in certain embodiments, ring B is

[0075] [ka]

[0076] [In the formula, R B is selected from the group consisting of hydrogen, -CH3, and -OCH3. In another embodiment, Ring B is

[0077] [ka]

[0078] wherein * represents the point of attachment to the -NH- group in formula I. In another embodiment, the compound of formula I has formula II:

[0079] [ka]

[0080] It may be expressed as: In some embodiments, the compounds disclosed herein are

[0081] [ka]

[0082] It is expressed as: In yet other embodiments, the compounds disclosed herein are

[0083] [ka]

[0084] It is expressed as: In yet other embodiments, the compounds disclosed herein are

[0085] [ka]

[0086] It is expressed as: In a further embodiment, the compounds disclosed herein are

[0087] [ka]

[0088] It is expressed as: In some embodiments, the compounds disclosed herein are

[0089] [ka]

[0090] It is expressed as: In other embodiments, the compounds disclosed herein are

[0091] [ka]

[0092] It is expressed as: In some embodiments, R X , R W and R V Each of C may be substituted with one or more deuterium atoms. 1~ C alkyl. For example, in certain embodiments, R X , R W and R V are each independently selected from -CH3 and -CD3.

[0093] In some embodiments, Y is selected from the group consisting of O, NH, NCH3, S, S(O), and S(O)2. In other embodiments, Y is O. In certain embodiments, Z is selected from O, NH, and NCH3. In other embodiments, Z is NH.

[0094] In some embodiments, R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, -CH3, and -CF3, or R 2 and R 3 together with the carbon to which they are attached to form a cyclopropyl.

[0095] In some embodiments, m is 1. In other embodiments, m is 2. In still other embodiments, n is 0. In further embodiments, n is 1. In certain embodiments, p is 1 and R 4 is hydroxyl or -CHOH.

[0096]

[0068] Formula III:

[0097] [ka]

[0098] [In the formula, Q is N and T is C, or Q is C and T is N, Q and T are each members of an aromatic heterocyclic ring system; V is N(R V ), W is N and X is N, or V is N and W is N(R V ), where X is N, or V is N, W is N, and X is N(R X ) or V is N and W is C(R W ), and X is N(R X ) or V is N(R V ), and W is C(R W ), where X is N, or V is N(R V ), W is N, and X is C(R X ) or V is N and W is N(R W ), and C is C(R X ) or V is C(R V ), and W is N(R W ), where X is N, or V is C(R V ), W is N, and X is N(R X ) or V is N and W is C(R W ), and X is C(R X ) or V is C(R V ), and W is C(R W ), where X is N, or V is O, W is N, and X is N(R X ) or V is C(R V ), W is N and X is O; V, W and X are each members of an aromatic heterocyclic ring system; Y is O, N(R a ), S(O) w , CH2, and a bond; R V , R W and R X are each independently hydrogen and C 1~ C6 alkyl, 1~ Each C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, and hydroxyl; R 1 is hydrogen or C 1~ C6 alkyl, C 1~ The C6 alkyl may be substituted with one or more halogens or deuterium. R 2 and R 3 are independently hydrogen, deuterium, and C 1~ C alkyl (optionally substituted with one or more halogens); or R 2 and R 3 may be bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl; R 4 Each occurrence independently represents deuterium, halogen, hydroxyl, -NR a R b , Cyano, C. 1~C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1~ C6 heteroalkyl, and C 1~ C alkoxy; R 4 may be substituted on available carbons with hydroxyl or one or more halogens; R 5 and R 6 are independently hydrogen, deuterium, and C 1~ C alkyl (optionally substituted with one or more halogens); or R 5 and R 6 may be bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl; R a and R b is independently selected for each occurrence from hydrogen and C 1~ C6 alkyl, 1~ The C6 alkyl may be substituted with one or more deuterium atoms; m is 1 or 2; n is 0 or 1, p is 0, 1, 2, 3 or 4; and w is 0, 1, or 2, or a pharma- ceutically acceptable salt and / or stereoisomer thereof.

[0099] In some embodiments, the compounds disclosed herein are

[0100] [ka]

[0101] It is expressed as: In other embodiments, the compounds disclosed herein are

[0102] [ka]

[0103] It is expressed as: In yet other embodiments, the compounds disclosed herein are

[0104] [ka]

[0105] It is expressed as: In a further embodiment, the compounds disclosed herein are

[0106] [ka]

[0107] It is expressed as: In some embodiments, the compounds disclosed herein are

[0108] [ka]

[0109] It is expressed as: In other embodiments, the compounds disclosed herein are

[0110] [ka]

[0111] It is expressed as: In some embodiments, R X , R W and R V Each of C may be substituted with one or more deuterium atoms. 1~ C alkyl. For example, in certain embodiments, R X , R W and R Vare each independently selected from -CH3 and -CD3. In other embodiments, Y is O.

[0112] In a further embodiment, R 1 C may be substituted with one or more deuterium atoms 1~ C alkyl. For example, in certain embodiments, R 1 is selected from -CH3 and -CD3.

[0113] In yet another embodiment, R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, -CH3, and -CF3, or R 2 and R 3 together with the carbon to which they are attached to form a cyclopropyl.

[0114] In some embodiments, R 5 and R 6 are each independently selected from the group consisting of hydrogen, deuterium, -CH3, and -CF3. In some embodiments, m is 1. In other embodiments, m is 2. In still other embodiments, n is 0. In further embodiments, n is 1. In certain embodiments, p is 1 and R 4 is hydroxyl or -CHOH.

[0115]

[0080] Formula IV:

[0116] [ka]

[0117] [In the formula, Q is N and T is C, or Q is C and T is N, Q and T are each members of an aromatic heterocyclic ring system; V is N(RV ), W is N and X is N, or V is N and W is N(R V ), where X is N, or V is N, W is N, and X is N(R X ) or V is N and W is C(R W ), and X is N(R X ) or V is N(R V ), and W is C(R W ), where X is N, or V is N(R V ), W is N, and X is C(R X ) or V is N and W is N(R W ), and C is C(R X ) or V is C(R V ), and W is N(R W ), where X is N, or V is C(R V ), W is N, and X is N(R X ) or V is N and W is C(R W ), and X is C(R X ) or V is C(R V ), and W is C(R W ), where X is N, or V is O, W is N, and X is N(R X ) or V is C(R V ), W is N and X is O; V, W and X are each members of an aromatic heterocyclic ring system; Y is O, N(R a ), S(O) w , CH2, and a bond; R V , R W and R X are each independently hydrogen and C1~ C6 alkyl, 1~ Each C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, and hydroxyl; R 1 is hydrogen or C 1~ C6 alkyl, C 1~ The C6 alkyl may be substituted with one or more deuterium atoms; R 2 and R 3 are independently hydrogen, deuterium, and C 1~ C alkyl (optionally substituted with one or more halogens); or R 2 and R 3 may be bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl; R 4 Each occurrence independently represents deuterium, halogen, hydroxyl, -NR a R b , Cyano, C. 1~ C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1~ C6 heteroalkyl, and C 1~ C alkoxy; R 4 may be substituted on available carbons with hydroxyl or one or more halogens; R a and R b is independently selected for each occurrence from hydrogen and C 1~ C alkyl (optionally substituted with one or more halogens); m is 1 or 2; p is 0, 1, 2, 3 or 4; and w is 0, 1, or 2, or a pharma- ceutically acceptable salt and / or stereoisomer thereof.

[0118] In some embodiments, the compounds disclosed herein are

[0119] [ka]

[0120] It is expressed as: In other embodiments, the compounds disclosed herein are

[0121] [ka]

[0122] It is expressed as: In yet other embodiments, the compounds disclosed herein are

[0123] [ka]

[0124] It is expressed as: In a further embodiment, the compounds disclosed herein are

[0125] [ka]

[0126] It is expressed as: In some embodiments, the compounds disclosed herein are

[0127] [ka]

[0128] It is expressed as: In other embodiments, the compounds disclosed herein are

[0129] [ka]

[0130] It is expressed as: In some embodiments, R X , R W and R V Each of C may be substituted with one or more deuterium atoms. 1~ C alkyl. For example, in certain embodiments, R X , R W and R V are each independently selected from -CH3 and -CD3. In other embodiments, Y is O.

[0131] In a further embodiment, R 1 C may be substituted with one or more deuterium atoms 1~ C alkyl. For example, in certain embodiments, R 1 is selected from -CH3 and -CD3.

[0132] In yet another embodiment, R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, -CH3, and -CF3, or R 2 and R 3 together with the carbon to which they are attached to form a cyclopropyl.

[0133] In some embodiments, m is 1. In other embodiments, m is 2. In certain embodiments, p is 1 and R 4 is hydroxyl or -CHOH.

[0091] Formula V:

[0134] [ka]

[0135] [In formula: Q is N and T is C, or Q is C and T is N, Q and T are each members of an aromatic heterocyclic ring system; V is N(R V ), W is N and X is N, or V is N and W is N(R V ), where X is N, or V is N, W is N, and X is N(R X ) or V is N and W is C(R W ), and X is N(R X ) or V is N(R V ), and W is C(R W ), where X is N, or V is N(R V ), W is N, and X is C(R X ) or V is N and W is N(R W ), and C is C(R X ) or V is C(R V ), and W is N(R W ), where X is N, or V is C(R V ), W is N, and X is N(R X ) or V is N and W is C(R W ), and X is C(R X ) or V is C(R V ), and W is C(R W ), where X is N, or V is O, W is N, and X is N(R X ) or V is C(R V ), W is N and X is O; V, W and X are each members of an aromatic heterocyclic ring system; Z is N(R a) and O; R V , R W and R X are each independently hydrogen and C 1~ C6 alkyl, 1~ Each C6 alkyl is optionally independently substituted with one or more substituents selected from the group consisting of deuterium, halogen, and hydroxyl; R 1 is hydrogen or C 1~ C6 alkyl, C 1~ The C6 alkyl may be substituted with one or more deuterium atoms; R 2 and R 3 are independently hydrogen, deuterium, and C 1~ C alkyl (optionally substituted with one or more halogens); or R 2 and R 3 may be bonded together with the carbons to which they are attached to form a C3-C6 cycloalkyl; R 4 Each occurrence independently represents deuterium, halogen, hydroxyl, -NR a R b , Cyano, C. 1~ C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1~ C6 heteroalkyl, and C 1~ C alkoxy; R 4 may be substituted on available carbons with hydroxyl or one or more halogens; R a and R b is independently selected for each occurrence from hydrogen and C 1~ C6 alkyl, 1~ The C6 alkyl may be substituted with one or more deuterium atoms; m is 1 or 2; and p is 0, 1, 2, 3, or 4, or a pharma- ceutically acceptable salt and / or stereoisomer thereof.

[0136] In some embodiments, the compounds disclosed herein are

[0137] [ka]

[0138] It is expressed as: In other embodiments, the compounds disclosed herein are

[0139] [ka]

[0140] It is expressed as: In yet other embodiments, the compounds disclosed herein are

[0141] [ka]

[0142] It is expressed as: In a further embodiment, the compounds disclosed herein are

[0143] [ka]

[0144] It is expressed as: In some embodiments, the compounds disclosed herein are

[0145] [ka]

[0146] It is expressed as: In other embodiments, the compounds disclosed herein are

[0147] [ka]

[0148] It is expressed as: In some embodiments, R X , R W and R V Each of C may be substituted with one or more deuterium atoms. 1~ C alkyl. For example, in certain embodiments, R X , R W and R V are each independently selected from -CH3 and -CD3. In other embodiments, Z is NH.

[0149] In a further embodiment, R 1 C may be substituted with one or more deuterium atoms 1~ C alkyl. For example, in certain embodiments, R 1 is selected from -CH3 and -CD3.

[0150] In yet another embodiment, R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, -CH3, and -CF3, or R 2 and R 3 together with the carbon to which they are attached to form a cyclopropyl.

[0151] In some embodiments, m is 1. In other embodiments, m is 2. In certain embodiments, p is 1 and R 4 is hydroxyl or -CHOH.

[0102] Also disclosed herein is a compound selected from any of the compounds shown in Table 1, or a pharma- ceutically acceptable salt and / or stereoisomer thereof.

[0152] [Table 1-1]

[0153] [Table 1-2]

[0154] [Table 1-3]

[0155] [Table 1-4]

[0156] [Table 1-5]

[0157] [Table 1-6]

[0158] 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, each center being in 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 of enantiomers and / or diastereoisomers resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, 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, separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomers are then recovered along with the resolving agent. labeled compound

[0104] In some embodiments, the compounds described herein exist in their isotopically labeled forms. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to the compounds listed herein except for the fact that one or more atoms have been replaced with an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into the compounds described herein, or their solvates, or stereoisomers, 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 Compounds described herein that contain the above-mentioned isotopes and / or other isotopes of other atoms, and pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, are within the scope of the present disclosure. Certain isotopically labeled compounds, e.g., those that contain radioactive isotopes, e.g., 3 H and 14 Compounds incorporating C are useful in drug and / or substrate tissue distribution assays. Tritium-labeled, i.e. 3 H and carbon-14, i.e. 14 Isotopes such as C are particularly preferred due to their ease of preparation and detectability. Additionally, heavier isotopes such as deuterium, i.e. 2Substitution with H provides certain therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compound, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is prepared by any suitable method.

[0159]

[0105] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Pharmaceutically acceptable salts

[0106] In some embodiments, the compounds described herein are present as their pharma- ceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharma- ceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharma- ceutically acceptable salts as pharmaceutical compositions.

[0160]

[0107] 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, as well as inorganic and organic acids, to form pharma- ceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting the purified compounds in their free form with the appropriate acid or base and isolating the salt thus formed.

[0161]

[0108] Examples of pharma- ceutically acceptable salts include those 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, 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-hisulfate, hydroxybenzo ... The salts include hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undeconate, and xylenesulfonate.

[0162] Additionally, the compounds described herein can be prepared as pharma- ceutically acceptable salts formed by reacting the free base form of the compound with a pharma- ceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like, as well as organic acids such as, for example, 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-hydroxyphenyl)-2-methyl-2-propanediol, 3-(4-hydroxyphenyl) ... These include arylsulfonic acid, methanesulfonic acid, ethanesulfonic 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, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0163]

[0110] In some embodiments, compounds described herein containing free acid groups are reacted with a suitable base, such as hydroxide, carbonate, bicarbonate, or sulfate of a pharma-ceutically acceptable metal cation, with ammonia, or with a pharma-ceutically 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 examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1~4 alkyl)4, etc.

[0164] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It will be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. solvate

[0112] 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.

[0165]

[0113] A solvate contains a stoichiometric or non-stoichiometric amount of a solvent, such as water, ethanol, etc. A hydrate is formed when the solvent is water, or an alcoholate is 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 herein 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 herein. Tautomers

[0114] In some circumstances, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by the migration of a hydrogen atom with the switching of a single bond and adjacent double bond. In bond configurations where tautomerization is possible, chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Pharmaceutical Compositions In certain embodiments, the compounds described herein are administered as pure chemicals. In some embodiments, the compounds described herein are combined with a pharma- ceutically suitable or acceptable carrier (also referred to herein as a pharma- ceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), selected based on the selected route of administration and standard pharmaceutical practice, e.g., as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed., Mack Pub. Co., Easton, PA (2005)).

[0166]

[0116] Thus, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a pharma- ceutically acceptable excipient.

[0167]

[0117] In certain embodiments, the compounds provided herein are substantially pure in the sense that they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, e.g., unreacted intermediates or synthetic by-products produced in one or more steps of a synthetic method.

[0168]

[0118] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented). The appropriate dose and the appropriate duration and frequency of administration are determined by factors such as the condition of the patient, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. In general, the appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide a therapeutic and / or prophylactic benefit, for example, improved clinical outcome, for example, more frequent, complete or partial remission, or longer disease-free and / or overall survival, or a reduction in the severity of symptoms. The optimal dose is generally determined using experimental models and / or clinical trials. The optimal dose depends on the patient's body mass, weight, or blood volume.

[0169] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including oral buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal, and epidural and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, intranasal, topical, or ophthalmic 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 solution, 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.

[0170]

[0120] The appropriate dose and dosage regimen are determined by conventional titration techniques known to those skilled in the art. Generally, treatment is initiated with a small dose that is lower than the optimal dose of the compounds disclosed herein. The dose is then increased in small increments until the optimal effect under the circumstances is reached. In some embodiments, the method of the present invention includes administration of at least one compound disclosed herein at about 0.1 μg to about 50 mg per kg of subject body weight. For a 70 kg patient, a dose of the compounds disclosed herein at about 10 μg to about 200 mg is more commonly used, depending on the physiological response of the subject.

[0171]

[0121] By way of example only, doses of the compounds described herein for the methods for treating the diseases described herein are from about 0.001 to about 1 mg / kg (body weight of the subject) 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 / kg (body weight) per day. In some embodiments, the dose of a compound described herein for the methods described is from about 1 to about 1000 mg / kg (of the body weight of the subject undergoing treatment) 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. Treatment Method The compounds disclosed herein, or pharma- ceutically 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.

[0172] Provided herein are compounds that are useful as inhibitors of TYK2 and therefore for treating one or more disorders associated with the activity of TYK2 or a mutant thereof.

[0124] Provided herein is a method for treating a disease or disorder, wherein the disease or disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-associated disorder, the method comprising administering to a patient in need of treatment for the disease or disorder a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0173] In some embodiments, the disease or disorder is an autoimmune disorder. In 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.

[0174] In some embodiments, the disease or disorder is an inflammatory disorder. In some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, or inflammatory bowel disease.

[0175]

[0127] In some embodiments, the disease or disorder is a proliferative disorder. In some embodiments, the proliferative disorder is cancer. In some embodiments, the disease or disorder is a proliferative disorder. In some embodiments, the proliferative disorder is a hematological cancer. In some embodiments, the proliferative disorder 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 disorder is polycythemia vera, myelofibrosis, essential thrombocytosis or thrombocytosis.

[0176]

[0128] In some embodiments, the disease or disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon syndrome, or type 1 diabetes.

[0177] In some embodiments, the disease or disorder is a neurological disorder, hi some embodiments, the neurological disorder is Alzheimer's disease. In some embodiments, the proliferation disorder is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation to 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.

[0178] In some embodiments, the disease or disorder is associated with transplantation. In some embodiments, the disease or disorder is associated with transplantation is transplant rejection, or graft-versus-host disease. 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.

[0179]

[0133] Provided herein are methods for treating inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo vulgaris, 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.

[0180] Methods for treating other diseases or conditions, e.g., diseases or conditions having an inflammatory component, e.g., treatment of ocular diseases and conditions, e.g., ocular allergies, conjunctivitis, sicca, and diseases affecting the nose, including vernal conjunctivitis, allergic rhinitis, and inflammatory diseases in which the involvement of an autoimmune reaction is suggested or which have an autoimmune component or cause, including autoimmune blood diseases (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, granulamatosis), dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, pulmonary hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity lung disease inflammation, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjögren's syndrome, dry conjunctivitis and vernal conjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic-onset 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 disease) change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis, kidney disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle fatigue, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and nonallergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, rhinosinusitis,Ocular allergies, silica-induced disease, COPD (damage, airway inflammation, bronchial hyperresponsiveness, remodeling or reduced disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis Provided herein are methods for treating inflammatory bowel disease, endometritis, enteritis, enteritis, epicondylitis, epididymitis, fasciitis, connectivitis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0181]

[0135] In some embodiments, the inflammatory disease is acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndromes (CAPS), or osteoarthritis.

[0182] 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).

[0183]

[0137] In some embodiments, the inflammatory disease is Sjogren's syndrome, an allergic disease, osteoarthritis, an eye condition such as eye allergy, conjunctivitis, dry conjunctivitis, vernal conjunctivitis, or a disease affecting the nose such as allergic rhinitis.

[0184]

[0138] For example, 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 therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition disclosed herein.

[0185] Also disclosed herein is a method of inhibiting TYK2 activity in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a disclosed compound or a pharmaceutical composition disclosed herein. In some embodiments, the inhibition of TYK2 activity is associated with treating a disease or disorder selected from the group consisting of, for example, Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis.

[0186] Further disclosed herein is a method for treating a TYK2-mediated disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a disclosed compound or pharmaceutical composition. In some embodiments, the contemplated TYK2-mediated disorder may be, for example, an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In other embodiments, the contemplated disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.

[0187] For example, provided herein is a method of treating one or more of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis in a patient in need of treatment, comprising administering to the patient an effective amount of any one of the compounds disclosed herein, or the disclosed pharmaceutical compositions. Combination therapy

[0142] In certain instances, the compounds described herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, are administered in combination with a second therapeutic agent.

[0188]

[0143] In some embodiments, the benefit received by the patient is increased by administering one of the compounds described herein with a second therapeutic agent (including also a therapeutic regimen) that also has a therapeutic benefit.

[0189]

[0144] In one particular embodiment, a compound described herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharma- ceutically 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.

[0190]

[0145] In any event, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient is simply the sum of the two therapeutic agents, or the patient experiences a synergistic benefit.

[0191] In certain embodiments, different therapeutically effective dosages of the compounds disclosed herein are utilized in the formulation of pharmaceutical compositions and / or treatment regimens when the compounds disclosed herein are administered in combination with a second therapeutic agent. The therapeutically effective dosages of drugs and other agents for use in combination treatment regimens may be determined by means similar to those described herein above for the active substances themselves. Additionally, the prevention / treatment methods described herein include the use of regular dosing, i.e., providing more frequent, lower doses to minimize toxic side effects. In some embodiments, combination treatment regimens include treatment regimens in which administration of the compounds described herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is initiated before, during, or after treatment with a second agent described herein, and continues at any time during or after treatment with the second agent. Combination treatment regimens also include treatments in which the compound described herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and the second agent used in combination are administered at the same time or at different times, and / or the intervals between treatments are reduced or increased.Combination treatments further include cyclical treatments that are started and stopped at different times to aid in the clinical management of the patient.

[0192]

[0147] It is understood that dosage regimens for treating, preventing, or ameliorating the condition(s) for which relief is sought will be modified according to a variety of factors (e.g., the disease, disorder, or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some cases, the dosage regimen actually utilized will vary and, in some embodiments, will deviate from the dosage regimens set forth herein.

[0193] For the combination therapies described herein, the dosage of the co-administered compound will vary depending on the type of codrug utilized, the particular drug utilized, the disease or condition being treated, etc. In additional embodiments, when co-administered with a second therapeutic agent, the compounds provided herein are administered simultaneously or sequentially with the second therapeutic agent.

[0194] In combination therapy, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. When administration is simultaneous, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills), by way of example only.

[0195] The compounds described herein, or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, and combination therapies are administered before, during, or after the onset of a disease or condition, and the timing of administering a composition containing the compound varies. Thus, in one embodiment, the compounds described herein are used prophylactically and administered continuously to a subject 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 possible after the onset of a disease or condition is detected or suspected, for the time required for the treatment of the disease. In some embodiments, the length of time required for treatment varies, and the length of time of treatment is adjusted to suit the particular needs of each subject. For example, in certain embodiments, the compounds described herein or formulations containing the compounds are administered for at least 2 weeks, about 1 month to about 5 years.

[0196] In some embodiments, the compounds described herein, or their pharma- ceutically acceptable salts, solvates, or stereoisomers, 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., the adjuvant has a minimal therapeutic benefit by itself, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). EXAMPLES

[0197]

[0152] The compounds described herein can be prepared in several ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it should be understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration and work-up procedures, can be selected to be standard conditions for the reaction, unless otherwise indicated. It is understood by those skilled in the art of organic synthesis that the functional groups present on the various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents that are not compatible with the reaction conditions will be apparent to those skilled in the art, and alternate methods are therefore shown. The starting materials for the examples are commercially available or easily prepared by standard methods from known materials. At least some of the compounds identified herein as "intermediates" are envisioned as compounds of the present disclosure.

[0198] Example 1 (6 1 R,6 2 R,E)-3 1 -Methyl-1 8 -(Methylamino)-3 1 Synthesis of H-5-oxa-2,7-diaza-1(6,3),3(4,6)-diimidazo[1,2-b]pyridazina-6(1,2)-cyclopentaneacyclooctaphan-8-one (compound 1)

[0199] [ka]

[0200] To a stirred solution of (7-bromo-3-methyl-1,2,3-benzotriazol-5-yl)methyl methanesulfonate (1.6 g, 5.0 mmol, 1 equiv.) and tert-butyl N-[(1R,2R)-2-hydroxycyclopentyl]carbamate (2 g, 10 mmol, 2 equiv.) in THF (10 mL) was added TBAI (184 mg, 0.50 mmol, 0.1 equiv.) and NaH (0.14 g, 6 mmol, 1.2 equiv.) in portions at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 0° C. under nitrogen atmosphere for 3 h. The desired product could be detected by LCMS. The reaction was quenched with water at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 60% to 70% gradient over 10 min; detector, UV 254 nm. This gave tert-butyl N-[(1R,2R)-2-[(7-bromo-3-methyl-1,2,3-benzotriazol-5-yl)methoxy]cyclopentyl]carbamate (1.2 g, 55%) as a white solid.

[0201] To a stirred solution of tert-butyl N-[(1R,2R)-2-[(7-bromo-3-methyl-1,2,3-benzotriazol-5-yl)methoxy]cyclopentyl]carbamate (1.2 g, 2.7 mmol, 1 eq.) and tert-butyl carbamate (480 mg, 4 mmol, 1.5 eq.) in dioxane (10 mL) was added Pd2(dba)3 (250 mg, 0.27 mmol, 0.1 eq.), Xantphos (315 mg, 0.55 mmol, 0.2 eq.) and Cs2CO3 (1770 mg, 5.5 mmol, 2 eq.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100° C. overnight under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The desired product could be detected by LCMS. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 50% to 75% gradient over 20 min; detector, UV 254 nm. This gave tert-butyl N-[6-(([(1R,2R)-2-[(tert-butoxycarbonyl)amino]cyclopentyl]oxymethyl)-1-methyl-1,2,3-benzotriazol-4-yl]carbamate (1 g, 85%) as a green solid.

[0202] A solution of tert-butyl N-[6-(([(1R,2R)-2-[(tert-butoxycarbonyl)amino]cyclopentyl]oxymethyl)-1-methyl-1,2,3-benzotriazol-4-yl]carbamate (750 mg, 1.63 mmol, 1 equiv) and 4 M HCl in 1,4-dioxane (15 mL) was stirred at room temperature under nitrogen atmosphere for 3 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was used directly in the next step without further purification.

[0203] To a stirred solution of 6-(([(1R,2R)-2-aminocyclopentyl]oxymethyl)-1-methyl-1,2,3-benzotriazol-4-amine (250 mg, 0.96 mmol, 1 equiv.) and 8-[(tert-butoxycarbonyl)(methyl)amino]-6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid (375 mg, 1.2 mmol, 1.2 equiv.) in DCM (5 mL) was added DIEA (989 mg, 7.7 mmol, 8 equiv.) and HATU (545 mg, 1.4 mmol, 1.5 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 30% to 70% gradient in 20 min; detector, UV 254 nm. This gave tert-butyl N-(3-([(1R,2R)-2-[(7-amino-3-methyl-1,2,3-benzotriazol-5-yl)methoxy]cyclopentyl]carbamoyl-6-chloroimidazo[1,2-b]pyridazin-8-yl)-N-methylcarbamate (425 mg, 78%) as a yellow solid.

[0204] To a stirred solution of tert-butyl N-(3-([(1R,2R)-2-[(7-amino-3-methyl-1,2,3-benzotriazol-5-yl)methoxy]cyclopentyl]carbamoyl-6-chloroimidazo[1,2-b]pyridazin-8-yl)-N-methylcarbamate (385 mg, 0.68 mmol, 1 equiv.) and Pd2(dba)3 (62 mg, 0.07 mmol, 0.1 equiv.) in dioxane (8 mL) was added Xantphos (78 mg, 0.14 mmol, 0.2 equiv.) and Na2CO3 (143 mg, 1.3 mmol, 2 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C under nitrogen atmosphere overnight. The desired product was determined by LCMS. could be detected. The mixture was allowed to cool to room temperature. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 60% to 70% gradient over 10 min; detector, UV 254 nm. This gave tert-butyl N-methyl-N-[(13R,17R)-7-methyl-19-oxo-12-oxa-2,5,6,7,18,22,26,27-octaazahexacyclo[18.5.2.1^(3,10.0^(4,8.0^(13,17.0^(23,27]octacosa-1(26),3,5,8,10(28),20,22,24-octaen-24-yl]carbamate (310 mg, 86%) as a yellow solid.

[0205] tert-Butyl N-methyl-N-[(13R,17R)-7-methyl-19-oxo-12-oxa-2,5,6,7,18,22,26,27-octaazahexacyclo[18.5.2.1^(3,10.0^(4,8.0^(13,17.0^(23,27]octacosa-1(26),3,5,8,10(28),20,22,24-octaen-24-yl]carbamate (280 mg, 0.53 mmol, 1 equiv.) and 4M A solution of HCl in 1,4-dioxane (10 mL) was stirred at room temperature under nitrogen atmosphere for 3 hours. The desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 30% to 70% gradient in 20 minutes; detector, UV 254 nm. This afforded (13R,17R)-7 -Methyl-24-(methylamino)-12-oxa-2,5,6,7,18,22,26,27-octaazahexacyclo[18.5.2.1^(3,10.0^(4,8.0^(13,17.0^(23,27]octacos-1(26),3,5,8,10(28),20,22,24-octaen-19-one (71 mg, 31%) was obtained as a white solid. LCMS: [M+H]+=434.10.

[0206]

number

[0207] Example 2 (1 3 E,1 4 E,6 1 R,6 2 R)-3 1 -Methyl-1 7 -(Methylamino)-3 1 Synthesis of H-5-oxa-2,7-diaza-1(5,3),3(4,6)-dipyrazolo[1,5-a]pyrimidina-6(1,2)-cyclopentaneacyclooctaphan-8-one (compound 2)

[0208] [ka]

[0209] Ethyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((6-((((1R,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)oxy)methyl)-1-methyl-1H-benzo[d][1,2,3]triazol-4-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (2c) To a solution of 2a (100 mg, 0.235 mmol, 1.00 equiv) in anhydrous dioxane (4.7 mL) was added 2b (86 mg, 0.25 mmol, 1.1 equiv), Cs2CO3 (153 mg, 0.470 mmol, 2.00 equiv), Pd2(dba)3 (21 mg, 0.024 mmol, 0.1 equiv) and BINAP (27 mg, 0.047 mmol, 0.20 equiv). The resulting mixture was stirred at reflux under N2 for 16 h. The mixture was concentrated under reduced pressure and purified by silica gel flash column chromatography (R f =0.65, DCM / MeOH, 95:5), affording 2c (132 mg, 83%) as a white solid. LCMS [M+H] + =680.21.

[0210]

number

[0211] 7-((tert-butoxycarbonyl)(methyl)amino)-5-((6-((((1R,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)oxy)methyl)-1-methyl-1H-benzo[d][1,2,3]triazol-4-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2d) To a solution of 2c (130 mg, 0.191 mmol, 1.00 equiv) in a mixture of THF / MeOH / water (1:1:1, 3.0 mL) was added LiOH monohydrate (80 mg, 1.9 mmol, 10 equiv). The reaction mixture was stirred at reflux for 16 h. The solvent was removed under reduced pressure. Purification by silica gel flash column chromatography (0-80% MeOH in DCM) afforded 2d (71 mg, 57%) as a white solid. LCMS [M+H] + =652.18. 5-((6-((((1R,2R)-2-aminocyclopentyl)oxy)methyl)-1-methyl-1H-benzo[d][1,2,3]triazol-4-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2e) To a solution of 2d (71 mg, 0.11 mmol, 1.0 equiv) in a mixture of DCM / THF (1:1, 2.0 mL) was added TFA (0.85 mL, 11 mmol, 100 equiv) at 0° C. The resulting mixture was stirred at room temperature for 2 h. The solution was concentrated under reduced pressure to give 2e (60 mg, quantitative yield) as a brown oil. [M+H] + =452.18. (1 3 E,1 4 E,6 1 R,6 2 R)-3 1 -Methyl-1 7 -(Methylamino)-3 1 H-5-oxa-2,7-diaza-1(5,3),3(4,6)-dipyrazolo[1,5-a]pyrimidina-6(1,2)-cyclopentane acyclooctaphan-8-one To a solution of 3e (50 mg, 0.11 mmol, 1.0 equiv) in a mixture of DCE (2.2 mL) and DMF (0.22 mL) was added HATU (42 mg, 0.11 mmol, 1.0 equiv) and DIEA (0.15 mL, 0.88 mmol, 8.0 equiv). The reaction mixture was stirred at room temperature for 2 h. The solution was quenched by the addition of water (2.0 mL), extracted with DCM (3×5 mL), dried over NaSO, and concentrated under reduced pressure. Purification by silica gel flash column chromatography gave (R f =0.45, DCM / MeOH, 95:5) to give the title compound (20 mg, 42%) as a white solid. 21 H 23 N9O2. MW: 433.48. LCMS: [M+H] + =434.12.

[0212]

number

[0213] Following synthetic experimental procedures similar to those described in Examples 1 and 2, the following compounds were prepared: (6 1 R,6 2 R,E)-3 1 -Methyl-1 8 -(Methylamino)-3 1 H-5-Oxa-2,7-diaza-1(6,3),3(7,5)-diimidazo[1,2-b]pyridazina-6(1,2)-cyclopentaneacyclooctaphan-8-one (compound 3)

[0214] [ka]

[0215]

[0164] White solid. f =0.40(DCM / MeOH, 95:5). Formula:C 21 H 23 N9O2. MW: 433.48. LCMS [M+H] + =434.20.

[0216]

number

[0217] (1 5 E,3 4 E,6 1 R,6 2 R)-3 2 -Methyl-1 8 -(Methylamino)-3 2 H-5-Oxa-2,7-diaza-1(6,3),3(4,6)-diimidazo[1,2-b]pyridazina-6(1,2)-cyclopentane acyclooctaphan-8-one (compound 4)

[0218] [ka]

[0219]

[0165] White solid. f =0.40(DCM / MeOH, 95:5). Formula:C 21 H 23 N9O2. MW: 433.48. LCMS: [M+H] + =434.33.

[0220]

number

[0221] (6 1 S,6 2 R,E)-3 1 -Methyl-1 8 -(Methylamino)-3 1 H-5-Oxa-2,7-diaza-1(6,3),3(4,6)-diimidazo[1,2-b]pyridazina-6(1,2)-cyclopentane acyclooctaphan-8-one (compound 5)

[0222] [ka]

[0223]

[0166] White solid. f =0.40(DCM / MeOH, 95:5). Formula:C 21 H 23 N9O2. MW: 433.48. LCMS: [M+H] + =434.18.

[0224]

number

[0225] (6 1 S,6 2 R,E)-3 1 -Methyl-1 8 -(Methylamino)-3 1 H-5-Oxa-2,7-diaza-1(6,3),3(7,5)-diimidazo[1,2-b]pyridazina-6(1,2)-cyclopentane acyclooctaphan-8-one (compound 6)

[0226] [ka]

[0227]

[0167] White solid. f =0.40(DCM / MeOH, 95:5). Formula:C 21 H 23 N9O2. MW: 433.48. LCMS: [M+H] + =434.20.

[0228]

number

[0229] (1 5 E,3 4 E,6 1 S,6 2 R)-3 2 -Methyl-1 8 -(Methylamino)-3 2H-5-Oxa-2,7-diaza-1(6,3),3(4,6)-diimidazo[1,2-b]pyridazina-6(1,2)-cyclopentaneacyclooctaphan-8-one (compound 7)

[0230] [ka]

[0231]

[0168] White solid. f =0.35(DCM / MeOH, 95:5). Formula:C 21 H 23 N9O2. MW: 433.48. LCMS: [M+H] + =434.20.

[0232]

number

[0233] (1 3 E,1 4 E,3 4 E,6 1 R,6 2 R)-3 2 -Methyl-1 7 -(Methylamino)-3 2 H-5-Oxa-2,7-diaza-1(5,3),3(4,6)-dipyrazolo[1,5-a]pyrimidina-6(1,2)-cyclopentaneacyclooctaphan-8-one (compound 10)

[0234] [ka]

[0235]

[0169] White solid. f =0.30(DCM / MeOH, 95:5). Formula:C 19 H 23 N9O2. MW: 433.48. LCMS: [M+H] + =434.12.

[0236]

number

[0237] (1 3 E,1 4 E,6 1 S,6 2 R)-3 1 -Methyl-1 7 -(Methylamino)-3 1 H-5-Oxa-2,7-diaza-1(5,3),3(4,6)-dipyrazolo[1,5-a]pyrimidina-6(1,2)-cyclopentaneacyclooctaphan-8-one (compound 11)

[0238] [ka]

[0239]

[0170] White solid. f =0.40(DCM / MeOH, 95:5). Formula:C 21 H 23 N9O2. MW: 433.48. LCMS: [M+H] + =433.99.

[0240]

number

[0241] (6 1 R,6 2 R,E)-3 1 -Methyl-1 8 -(Methylamino)-3 1 H-5-Oxa-2,7-diaza-1(6,3)-imidazo[1,2-b]pyridazina-3(4,6)-benzo[d]imidazola-6(1,2)-cyclopentane acyclooctaphan-8-one (compound 12)

[0242] [ka]

[0243]

[0171] White solid. f =0.35(DCM / MeOH, 95:5). Formula:C 22 H 24 N8O2. MW: 432.49. LCMS: [M+H] + =433.15.

[0244]

number

[0245] (6 1 S,6 2 R,E)-3 1 -Methyl-1 8 -(Methylamino)-3 1 H-5-Oxa-2,7-diaza-1(6,3)-imidazo[1,2-b]pyridazina-3(4,6)-benzo[d]imidazola-6(1,2)-cyclopentane acyclooctaphan-8-one (compound 13)

[0246] [ka]

[0247]

[0172] White solid. f =0.35(DCM / MeOH, 95:5). Formula:C 22 H 24 N8O2. MW: 432.49. LCMS: [M+H] + =433.08.

[0248]

number

[0249] Example 3 Synthesis of additional synthetic intermediates

[0173] Synthetic intermediates to certain disclosed compounds were prepared according to the following schemes a through g below.

[0250] [ka]

[0251] Example 5 TYK2 JH2 domain binding assay

[0174] Binding constants for the compounds described herein against the JH2 domain were determined with the following protocol for the KINOMEscan® assay (DiscoveRx). A fusion protein (amino acids G556 to D888 based on reference sequence NP_003322.3) of a partial-length construct of human TYK2 (JH2 domain-pseudokinase) 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) in the presence of Protease Inhibitor Cocktail Complete (Roche) and Phosphatase Inhibitor Cocktail Set II (Merck) according to the manufacturer's instructions. TYK2 (JH2 domain-pseudokinase) fusion protein was labeled with a chimeric double-stranded DNA tag containing an NFkB binding site condensed into the amplicon for qPCR readout and added directly to the expression extract (final concentration of DNA tag in binding reaction was 0.1 nM).

[0252] Streptavidin-coated magnetic beads (Dynal M280) were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resin binding assays. Ligand-bound 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 non-specific binding.

[0253] Binding reactions were made by combining 16 μl of DNA-tagged kinase extract, 3.8 μl of ligand-bound affinity beads, and 0.18 μl of test compound (PBS / 0.05% Tween20 / 10 mM DTT / 0.1% BSA / 2 μg / ml sonicated salmon sperm DNA). Extracts were used directly in the binding assay without any enzyme purification steps at >10,000-fold of all stock dilutions (final DNA-tagged enzyme concentration <0.1 nM). Extracts were loaded with DNA tags and diluted into the binding reaction in a two-step process. The first extract was diluted 1:100 in 1× binding buffer (PBS / 0.05% Tween20 / 10 mM DTT / 0.1% BSA / 2 μg / ml sonicated salmon sperm DNA) containing 10 nM DNA tags. The dilutions were equilibrated at room temperature for 15 minutes and then subsequently diluted 1:100 in 1× binding buffer. Test compounds were prepared as 111× stocks in 100% DMSO. Kd was determined using an 11-point 3-fold compound dilution series with three DMSO reference points. All compounds for Kd measurements were dispensed by acoustic transfer (non-contact dispense) in 100% DMSO. Compounds were then diluted to a final DMSO concentration of 0.9% and used directly in the assay. All reactions were performed in polypropylene 384-well plates. Each was in a final volume of 0.02 mL. Assay materials were incubated with shaking for 1 hour at room temperature. Beads were then pelleted and washed with wash buffer (1× PBS, 0.05% Tween 20) to remove displaced kinase and test compounds. The washed substrate was resuspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. Kinase concentration in the eluate was measured by qPCR. qPCR reactions were made 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 hot start at 95°C for 10 minutes, followed by 35 cycles of 95°C for 15 seconds and 60°C for 1 minute.

[0254] 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 reference points. All compounds for Kd measurements were dispensed by acoustic transfer (non-contact dispense) in 100% DMSO. Compounds were then diluted to a final DMSO concentration of 0.9% and used directly in the assay. A top compound concentration of 30,000 nM was used to determine Kd. Kd measurements were performed in duplicate.

[0255]

[0178] Hill equation:

[0256]

number

[0257] The binding constant (Kd) was calculated using a standard dose-response curve. The Hill slope was set to -1. Curves were fitted using a non-linear, least-squares fit using the Levenberg-Marquardt algorithm (Levenberg, K., A method for the solution of certain non-linear problems in least squares, Q. Appl. Math. 2, pp. 164-168 (1944)).

[0258]

[0180] The results are shown in Table 2. Example 5 INFα-induced pSTAT5 in human PBMCs Fresh human PBMCs were resuspended in RPMI 1640 medium with 10% FBS. Cells were seeded in 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 at 37°C for 1 hour. Human INFα recombinant protein (R&D Systems) was then added to the wells at a final concentration of 5000 units / ml and incubated at 37°C for 15 minutes. Cell lysates were prepared and analyzed with the Phospho STAT5(Tyr693)Kit (Meso Scale Discovery) according to the manufacturer's protocol.

[0259]

[0182] The calculation of the rate of inhibition is: relative pSTAT5 signal in each well = pSTAT5 signal in each well - mean pSTAT5 signal of baseline.

[0183] % Inhibition = (mean pSTAT5 signal in IFNα-treated wells - relative value of pSTAT5 signal in wells containing each compound) / mean pSTAT5 signal in IFNα-treated wells * 100%

[0184] Curves were plotted as % inhibition (y-axis) versus compound concentration (x-axis) and fitted with log(inhibitor) versus normalized response-variable slope by GraphPad Prism 7.0.

[0260]

[0185] The results are shown in Table 3.

[0261] [Table 2]

[0262] [Table 3]

[0263] Incorporation by Reference All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In the case of conflict, the present application, including any definitions herein, will control. Equivalents and Scope

[0186] Articles in the claims, such as "a," "an," and "the," may mean one or more than one, unless specifically indicated to the contrary or clear from the context. A claim or specification containing "or" between one or more members of a group is considered to be satisfied so long as one, more than one, or all of the members of the group are present in, utilized in, or relevant to a given product or process, unless specifically indicated to the contrary or clear from the context. The invention includes embodiments in which exactly one member of a group is present in, utilized in, or relevant to a given product or process. The invention includes embodiments in which more than one or all of the members of a group are present in, utilized in, or relevant to a given product or process.

[0264]

[0187] Furthermore, the present invention encompasses all variations, combinations, and permutations of one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims when they are introduced into another claim. For example, any claim that depends on another claim can be amended to include one or more limitations found in any other claim that depends on the same base claim. When elements are presented as a list, e.g., in Markush group format, each subgroup of elements is also disclosed, and any element(s) may be removed from the group. In general, when the invention, or aspects of the invention, are referred to as comprising certain elements and / or features, it is to be understood that certain embodiments of the invention or aspects of the invention consist of or consist essentially of such elements and / or features. For simplicity, these embodiments have not been specifically described in this language herein. It is also noted that the terms "comprise" and "contain" are intended to be open and permit the inclusion of additional elements or steps. When ranges are given, the endpoints are included. Furthermore, unless otherwise indicated or apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can assume any specific value or subrange within the ranges stated in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0265]

[0188] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and the present specification, the present specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be excluded even if the exclusion is not expressly set forth herein, since they are deemed to be known to those skilled in the art. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0266]

[0189] Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments of the invention described herein is not intended to be limited to the above specification, but rather as set forth in the appended claims. Those skilled in the art will recognize that various changes and modifications can be made to this specification without departing from the spirit or scope of the invention as defined in the following claims.

Claims

1. Formula I: 【Chemistry 1】 [In the formula, Ring A is a 6,5 ​​or 6,6 fused bicyclic heteroaryl containing 2, 3, or 4 ring nitrogens; R Ａ is independently each occurrence hydrogen, halogen, -NR ａ R ｂ , C １～ C ６ Alkyl, and C １～ C ６ alkoxy; １～ C ６ Alkyl and C １～ C ６ The alkoxy may be optionally substituted with one or more halogens or deuterium. Ring B is a 6,5 ​​or 6,6 fused bicyclic heteroaryl containing 1, 2 or 3 ring nitrogens; R Ｂ is independently each occurrence hydrogen, halogen, -NR ａ R ｂ , C １～ C ６ Alkyl, and C １～ C ６ alkoxy; １～ C ６ Alkyl and C １～ C ６ The alkoxy may be optionally substituted with one or more halogens or deuterium. Y is O, N(R ａ ), S(O) ｗ , C.H. ２ and a bond; Z is N(R ａ ) and O; R １ is independently selected from each occurrence of deuterium, halogen, hydroxyl, -NR ａ R ｂ , Cyano, C. １～ C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １～ C ６ Heteroalkyl, and C １～ C ６ alkoxy; R ４ may be substituted on available carbons with hydroxyl or one or more halogens; R ２ and R ３ are each independently hydrogen, deuterium, and C １～ C ６ alkyl (optionally substituted with one or more halogens); or R ２ and R ３ are bonded together with the carbon to which they are attached to form C ３ ~C ６ may form a cycloalkyl, R ａ and R ｂ is independently selected for each occurrence from hydrogen and C １～ C ６ alkyl, C １～ C ６ The alkyl may be substituted with one or more halogens or deuterium. m is 1 or 2; n is 0 or 1; p is 0, 1, 2, 3 or 4; and w is 0, 1 or 2, or a pharma- ceutically acceptable salt and / or stereoisomer thereof.

2. Ring A is 【Chemistry 2】 [In the formula, Q is N and T is C, or Q is C and T is N; R Ａ is -N(H)CH ３ , -NH ２ , hydrogen, and -OCH ３ is selected from the group consisting of The compound of claim 1, wherein * represents the point of attachment to the -NH- group in formula I.

3. Ring A is 【Chemistry 3】 3. The compound according to claim 1 or 2, selected from the group consisting of:

4. Ring A is 【Chemistry 4】 [In the formula, T is N or CH; R Ａ１ is -N(H)CH ３ , -NH ２ , hydrogen, and -OCH ３ is selected from the group consisting of R Ａ２ is hydrogen and -CH ３ is selected from the group consisting of The compound of claim 1, wherein * represents the point of attachment to the -NH- group in formula I.

5. Ring A is 【Chemistry 5】 5. The compound according to claim 1 or 4, selected from the group consisting of:

6. Ring B is 【Chemistry 6】 [In the formula, V is N (R Ｖ ), W is N and X is N; or V is N and W is N(R Ｖ ) where X is N; or V is N, W is N, and X is N(R Ｘ ) or V is N and W is C(R Ｗ ), and X is N(R Ｘ ) or V is N (R Ｖ ), and W is C(R Ｗ ) where X is N; or V is N (R Ｖ ), W is N, and X is C(R Ｘ ) or V is N and W is N(R Ｗ ), and C is C(R Ｘ ) or V is C(R Ｖ ), and W is N(R Ｗ ) where X is N; or V is C(R Ｖ ), W is N, and X is N(R Ｘ ) or V is N and W is C(R Ｗ ), and X is C(R Ｘ ) or V is C(R Ｖ ), and W is C(R Ｗ ) where X is N; or V is O, W is N, and X is N(R Ｘ ) or V is C(R Ｖ ), W is N and X is O; or V is O and W is C(R Ｗ ) where X is N; or V is N and W is C(R Ｗ ) and X is O; R Ｖ , R Ｗ and R Ｘ are each independently hydrogen and C １～ C ６ alkyl, C １～ C ６ each alkyl is optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, and hydroxyl; The compound according to any one of claims 1 to 5, wherein * represents the point of attachment to the -NH- group in formula I.

7. Ring B is 【Chemistry 7】 [In the formula, R Ｖ , R Ｗ and R Ｘ are each independently hydrogen, -CH ３ , and -CD ３ The compound according to any one of claims 1 to 6, wherein the compound is selected from the group consisting of:

8. Ring B is 【Chemistry 8】 [In the formula, R Ｖ , R Ｗ and R Ｘ are each independently hydrogen, -CH ３ , and -CD ３ The compound according to any one of claims 1 to 6, wherein the compound is selected from the group consisting of:

9. Ring B is 【Chemistry 9】 [In the formula, U, V, W, X, Y, and Z each independently represent N and C(R Ｂ wherein one or two of U, V, W, X, Y, and Z are N; R Ｂ is independently selected for each occurrence from hydrogen, halogen, C １～ C ３ Alkyl, and C １～ C ３ alkoxy; The compound according to any one of claims 1 to 5, wherein * represents the point of attachment to the -NH- group in formula I.

10. Ring B is 【Chemistry 10】 [In the formula, R Ｂ is hydrogen, -CH ３ , and -OCH ３ 10. The compound of any one of claims 1 to 5 and 9, selected from the group consisting of:

11. Ring B is 【Chemistry 11】 6. The compound of any one of claims 1 to 5, selected from the group consisting of: wherein * represents the point of attachment to the -NH- group in formula I.

12. Formula II: 【Chemistry 12】 The compound according to any one of claims 1, 2 and 6, wherein

13.

13. The compound according to claim 12, represented by:

14.

14. The compound according to claim 12, represented by:

15.

15. The compound according to claim 12, represented by:

16.

16. The compound according to claim 12, represented by:

17.

17. The compound according to claim 12, represented by:

18.

18. The compound according to claim 12, represented by:

19. R Ｘ , R Ｗ and R Ｖ are each hydrogen or C １～ C ６ 19. The compound of any one of claims 12 to 18, which is alkyl (optionally substituted with one or more deuteriums).

20. R Ｘ , R Ｗ and R Ｖ are each independently hydrogen, —CH ３ , and -CD ３ 20. The compound according to any one of claims 12 to 19, selected from the group consisting of:

21. Y is O, NH, NCH ３ , S, S(O), and S(O) ２ 21. The compound according to any one of claims 1 to 20, selected from the group consisting of:

22. 22. The compound according to any one of claims 1 to 21, wherein Y is O.

23. Z is O, NH, and NCH ３ 23. The compound according to any one of claims 1 to 22, selected from:

24. 24. The compound of any one of claims 1 to 23, wherein Z is NH.

25. R ２ and R ３ are each independently hydrogen, deuterium, or -CH ３ , and -CF ３ or R ２ and R ３ together with the carbon to which they are attached are linked to form a cyclopropyl.

26. 26. The compound according to any one of claims 1 to 25, wherein m is 1.

27. 26. The compound according to any one of claims 1 to 25, wherein m is 2.

28. 28. The compound according to any one of claims 1 to 27, wherein n is 0.

29. 28. The compound according to any one of claims 1 to 27, wherein n is 1.

30. p is 1, R ４ is hydroxyl or -CH ２ 30. The compound according to any one of claims 1 to 29, wherein R is OH.

31. Formula III: 【Chemistry 19】 [In the formula, Q is N and T is C, or Q is C and T is N; Q and T are each members of an aromatic heterocyclic ring system; V is N (R Ｖ ), W is N and X is N; or V is N and W is N(R Ｖ ) where X is N; or V is N, W is N, and X is N(R Ｘ ) or V is N and W is C(R Ｗ ), and X is N(R Ｘ ) or V is N (R Ｖ ), and W is C(R Ｗ ) where X is N; or V is N (R Ｖ ), W is N, and X is C(R Ｘ ) or V is N and W is N(R Ｗ ), and C is C(R Ｘ ) or V is C(R Ｖ ), and W is N(R Ｗ ) where X is N; or V is C(R Ｖ ), W is N, and X is N(R Ｘ ) or V is N and W is C(R Ｗ ), and X is C(R Ｘ ) or V is C(R Ｖ ), and W is C(R Ｗ ) where X is N; or V is O, W is N, and X is N(R Ｘ ) or V is C(R Ｖ ), W is N and X is O; V, W and X are each members of an aromatic heterocyclic ring system; Y is O, N(R ａ ), S(O) ｗ , C.H. ２ and a bond; R Ｖ , R Ｗ and R Ｘ are each independently hydrogen and C １～ C ６ alkyl, C １～ C ６ each alkyl is optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, and hydroxyl; R １ is hydrogen or C １～ C ６ alkyl, C １～ C ６ The alkyl may be substituted with one or more halogens or deuterium. R ２ and R ３ are each independently hydrogen, deuterium, and C １～ C ６ alkyl (optionally substituted with one or more halogens); or R ２ and R ３ are bonded together with the carbon to which they are attached to form C ３ ~C ６ may form a cycloalkyl, R ４ is independently selected from each occurrence of deuterium, halogen, hydroxyl, -NR ａ R ｂ , Cyano, C. １～ C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １～ C ６ Heteroalkyl, and C １～ C ６ alkoxy; R ４ may be substituted on available carbons with hydroxyl or one or more halogens; R ５ and R ６ are each independently hydrogen, deuterium, and C １～ C ６ alkyl (optionally substituted with one or more halogens); or R ５ and R ６ are bonded together with the carbon to which they are attached to form C ３ ~C ６ may form a cycloalkyl, R ａ and R ｂ is independently selected for each occurrence from hydrogen and C １～ C ６ alkyl, C １～ C ６ The alkyl may be substituted with one or more deuterium atoms; m is 1 or 2; n is 0 or 1; p is 0, 1, 2, 3 or 4; and w is 0, 1 or 2, or a pharma- ceutically acceptable salt and / or stereoisomer thereof.

32. 【Catalog 20】 The compound according to claim 31 ,

33. 【Chemical 21】 The compound according to claim 31 ,

34. 【Chemical 22】 The compound according to claim 31 ,

35. 【Chemical 23】 The compound according to claim 31 ,

36. 【Catalogue 24】 The compound according to claim 31 ,

37. 【Catalogue 25】 The compound according to claim 31 ,

38. R Ｘ , R Ｗ and R Ｖ each of which may be substituted with one or more deuterium atoms; １～ C ６ 38. The compound of any one of claims 31 to 37, which is alkyl.

39. R Ｘ , R Ｗ and R Ｖ each independently represents -CH ３ and -CD ３ 39. The compound according to any one of claims 31 to 38, selected from:

40. 40. The compound of any one of claims 31 to 39, wherein Y is O.

41. R １ C optionally substituted with one or more deuterium atoms １～ C ６ 41. The compound of any one of claims 31 to 40, which is alkyl.

42. R １ But -CH ３ and -CD ３ 42. The compound according to any one of claims 31 to 41, selected from:

43. R ２ and R ３ are each independently hydrogen, deuterium, or -CH ３ , and -CF ３ or R ２ and R ３ together with the carbon to which they are attached are linked to form a cyclopropyl.

44. R ５ and R ６ are each independently hydrogen, deuterium, or -CH ３ , and -CF ３ 44. The compound according to any one of claims 31 to 43, selected from the group consisting of:

45. 45. The compound of any one of claims 31 to 44, wherein m is 1.

46. 45. The compound according to any one of claims 31 to 44, wherein m is 2.

47. 47. The compound of any one of claims 31 to 46, wherein n is 0.

48. 47. The compound of any one of claims 31 to 46, wherein n is 1.

49. p is 1, R ４ is hydroxyl or -CH ２ 49. The compound according to any one of claims 31 to 48, wherein said compound is OH.

50. Formula IV: 【Chemistry 26】 [In the formula, Q is N and T is C, or Q is C and T is N; Q and T are each members of an aromatic heterocyclic ring system; V is N (R Ｖ ), W is N and X is N; or V is N and W is N(R Ｖ ) where X is N; or V is N, W is N, and X is N(R Ｘ ) or V is N and W is C(R Ｗ ), and X is N(R Ｘ ) or V is N (R Ｖ ), and W is C(R Ｗ ) where X is N; or V is N (R Ｖ ), W is N, and X is C(R Ｘ ) or V is N and W is N(R Ｗ ), and C is C(R Ｘ ) or V is C(R Ｖ ), and W is N(R Ｗ ) where X is N; or V is C(R Ｖ ), W is N, and X is N(R Ｘ ) or V is N and W is C(R Ｗ ), and X is C(R Ｘ ) or V is C(R Ｖ ), and W is C(R Ｗ ) where X is N; or V is O, W is N, and X is N(R Ｘ ) or V is C(R Ｖ ), W is N and X is O; V, W and X are each members of an aromatic heterocyclic ring system; Y is O, N(R ａ ), S(O) ｗ , C.H. ２ and a bond; R Ｖ , R Ｗ and R Ｘ are each independently hydrogen and C １～ C ６ alkyl, C １～ C ６ each alkyl is optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, and hydroxyl; R １ is hydrogen or C １～ C ６ alkyl, C １～ C ６ The alkyl may be substituted with one or more deuterium atoms; R ２ and R ３ are each independently hydrogen, deuterium, and C １～ C ６ alkyl (optionally substituted with one or more halogens); or R ２ and R ３ are bonded together with the carbon to which they are attached to form C ３ ~C ６ may form a cycloalkyl, R ４ is independently selected from each occurrence of deuterium, halogen, hydroxyl, -NR ａ R ｂ , Cyano, C. １～ C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １～ C ６ Heteroalkyl, and C １～ C ６ alkoxy; R ４ may be substituted on available carbons with hydroxyl or one or more halogens; R ａ and R ｂ is independently selected for each occurrence from hydrogen and C １～ C ６ alkyl (optionally substituted with one or more halogens); m is 1 or 2; p is 0, 1, 2, 3 or 4; and w is 0, 1 or 2, or a pharma- ceutically acceptable salt and / or stereoisomer thereof.

51. 【Chemical 27】 The compound according to claim 50, represented by:

52. 【Catalogue 28】 The compound according to claim 50, represented by:

53. 【Catalogue 29】 The compound according to claim 50, represented by:

54. 【Chemical 30】 The compound according to claim 50, represented by:

55. 【Chemical 31】 The compound according to claim 50, represented by:

56. 【Chemical 32】 The compound according to claim 50, represented by:

57. R Ｘ , R Ｗ and R Ｖ each of which may be substituted with one or more deuterium atoms; １～ C ６ 57. The compound of any one of claims 50 to 56, which is alkyl.

58. R Ｘ , R Ｗ and R Ｖ each independently represents -CH ３ and -CD ３ 58. The compound according to any one of claims 50 to 57, selected from:

59. 59. The compound of any one of claims 50 to 58, wherein Y is O.

60. R １ C optionally substituted with one or more deuterium atoms １～ C ６ 60. The compound of any one of claims 50 to 59, which is alkyl.

61. R １ But -CH ３ and -CD ３ 61. The compound according to any one of claims 50 to 60, selected from:

62. R ２ and R ３ are each independently hydrogen, deuterium, or -CH ３ , and -CF ３ or R ２ and R ３ together with the carbon to which they are attached are linked to form a cyclopropyl.

63. 63. The compound of any one of claims 50 to 62, wherein m is 1.

64. 63. The compound of any one of claims 50 to 62, wherein m is 2.

65. p is 1, R ４ is hydroxyl or -CH ２ 65. The compound of any one of claims 50 to 64, wherein:

66. Formula V: 【Chemical 33】 [In the formula, Q is N and T is C, or Q is C and T is N; Q and T are each members of an aromatic heterocyclic ring system; V is N (R Ｖ ), W is N and X is N; or V is N and W is N(R Ｖ ) where X is N; or V is N, W is N, and X is N(R Ｘ ) or V is N and W is C(R Ｗ ), and X is N(R Ｘ ) or V is N (R Ｖ ), and W is C(R Ｗ ) where X is N; or V is N (R Ｖ ), W is N, and X is C(R Ｘ ) or V is N and W is N(R Ｗ ), and C is C(R Ｘ ) or V is C(R Ｖ ), and W is N(R Ｗ ) where X is N; or V is C(R Ｖ ), W is N, and X is N(R Ｘ ) or V is N and W is C(R Ｗ ), and X is C(R Ｘ ) or V is C(R Ｖ ), and W is C(R Ｗ ) where X is N; or V is O, W is N, and X is N(R Ｘ ) or V is C(R Ｖ ), W is N and X is O; V, W and X are each members of an aromatic heterocyclic ring system; Z is N(R ａ ) and O; R Ｖ , R Ｗ and R Ｘ are each independently hydrogen and C １～ C ６ alkyl, C １～ C ６ each alkyl is optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, and hydroxyl; R １ is hydrogen or C １～ C ６ alkyl, C １～ C ６ The alkyl may be substituted with one or more deuterium atoms; R ２ and R ３ are each independently hydrogen, deuterium, and C １～ C ６ alkyl (optionally substituted with one or more halogens); or R ２ and R ３ are bonded together with the carbon to which they are attached to form C ３ ~C ６ may form a cycloalkyl, R ４ is independently selected from each occurrence of deuterium, halogen, hydroxyl, -NR ａ R ｂ , Cyano, C. １～ C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １～ C ６ Heteroalkyl, and C １～ C ６ alkoxy; R ４ may be substituted on available carbons with hydroxyl or one or more halogens; R ａ and R ｂ is independently selected for each occurrence from hydrogen and C １～ C ６ alkyl, C １～ C ６ The alkyl may be substituted with one or more deuterium atoms; m is 1 or 2; and p is 0, 1, 2, 3 or 4, or a pharma- ceutically acceptable salt and / or stereoisomer thereof. 【Request 67】 【Chemical 34】 The compound according to claim 66, represented by:

68. 【Chemical 35】 The compound according to claim 66, represented by:

69. 【Catalogue 36】 The compound according to claim 66, represented by: 【Request 70】 【Chemical 37】 The compound according to claim 66, represented by:

71. 【Catalogue 38】 The compound according to claim 66, represented by:

72. 【Catalogue 39】 The compound according to claim 66, represented by:

73. R Ｘ , R Ｗ and R Ｖ each of which may be substituted with one or more deuterium atoms; １～ C ６ 73. The compound of any one of claims 66 to 72, which is alkyl.

74. R Ｘ , R Ｗ and R Ｖ each independently represents -CH ３ and -CD ３ 74. The compound according to any one of claims 66 to 73, selected from:

75. R １ C optionally substituted with one or more deuterium atoms １～ C ６ 75. The compound of any one of claims 66 to 74, which is alkyl.

76. R １ But -CH ３ and -CD ３ 76. The compound according to any one of claims 66 to 75, selected from:

77. R ２ and R ３ are each independently hydrogen, deuterium, or -CH ３ , and -CF ３ or R ２ and R ３ together with the carbon to which they are attached are linked to form a cyclopropyl.

78. 78. The compound of any one of claims 66 to 77, wherein m is 1.

79. 78. The compound of any one of claims 66 to 77, wherein m is 2.

80. p is 1, R ４ is hydroxyl or -CH ２ 80. The compound of any one of claims 66 to 79, wherein said compound is OH. 【Request 81】 【Chemical 40-1】 【Chemistry 40-2】 【Chemistry 40-3】 or a pharma- ceutically acceptable salt and / or stereoisomer thereof.

82. 82. A pharmaceutical composition comprising a compound according to any one of claims 1 to 81, or a pharma- ceutically acceptable salt and / or stereoisomer thereof, and a pharma- ceutically acceptable excipient.

83. A method for inhibiting TYK2 enzyme in a patient or biological sample, comprising contacting the patient or biological sample with a therapeutically effective amount of a compound described in any one of claims 1 to 81, or a pharmaceutical composition described in claim 82.

84. A method for inhibiting TYK2 activity in a patient in need of inhibition of TYK2 activity, comprising administering to the patient a therapeutically effective amount of a compound described in any one of claims 1 to 81, or a pharmaceutical composition described in claim 82.

85. 85. The method of claim 84, wherein inhibition of TYK2 activity is associated with treating a disease or disorder selected from the group consisting of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis.

86. A method for treating a TYK2-mediated disorder in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a compound described in any one of claims 1 to 81, or a pharmaceutical composition described in claim 82.

87. 87. The method of claim 86, wherein the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-associated disorder.

88. 88. The method of claim 87, wherein the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.

89. A method of treating one or more of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis in a patient in need of such treatment, comprising administering to the patient an effective amount of any one of the compounds described in claims 1 to 81, or the pharmaceutical composition described in claim 82.

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