TYK2 inhibitor and application thereof

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 320,320, filed on March 16, 2022; the contents of which are hereby incorporated by reference in their entirety. Background Art

[0003] TYK2 is a non-receptor tyrosine kinase member of the JAK protein kinase family. The mammalian JAK family consists of four members, namely TYK2, JAK1, JAK2 and JAK3. JAK proteins (including TYK2) are an integral part of cytokine signal transduction. TYK2 is associated with the cytoplasmic domains of type I and type II cytokine receptors and type I and type III interferon receptors, and is activated by these receptors after cytokine binding. Cytokines associated with TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω and IFN-ζ (also known as limitin)) and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, L-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF). Activated TYK2 then goes on to phosphorylate other signaling proteins, such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

[0004] IL-23 activates TYK2, which is associated with inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. A genome-wide association study of 2,622 psoriasis patients found an association between disease susceptibility and TYK2. Knockout or inhibition of TYK2 tyrosine phosphorylation inhibitors significantly reduced IL-23- and IL-22-induced dermatitis.

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

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

[0007] Compared to controls, TYK2 knockout mice were completely resistant to experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), with no CD4 T cell infiltration in the spinal cord, indicating that TYK2 is essential for the development of pathogenic CD4-mediated disease in MS. This confirms earlier studies linking increased TYK2 expression to MS susceptibility. TYK2 loss-of-function mutations lead to reduced demyelination and increased neuronal remyelination, further suggesting a role for TYK2 inhibitors in the treatment of MS and other demyelinating diseases of the central nervous system.

[0008] TYK2 is the only signal messenger shared by IL-12 and IL-23. TYK2 knockout reduces the footpad thickness induced by methylated BSA injection, psoriasis-like skin inflammation induced by imiquimod, and colitis induced by dextran sulfate sodium or 2,4,6-trinitrobenzenesulfonic acid in mice.

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

[0010] TYK2 has been shown to play an important role in maintaining tumor surveillance, and TYK2 knockout mice exhibit impaired cytotoxic T cell responses and accelerated tumor development. However, these effects are associated with potent suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors are well suited for the treatment of autoimmune diseases or transplant rejection. Although other JAK family members, such as JAK3, have similar roles in the immune system, TYK2 is considered a better target because it participates in fewer and more closely related signaling pathways, resulting in fewer off-target effects.

[0011] Studies in T-cell acute lymphoblastic leukemia (T-ALL) have shown that T-ALL is highly dependent on IL-10 signaling through TYK2 via STAT1 to maintain cancer cell survival by upregulating the anti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, reduces cell growth. Specific activating mutations against TYK2 that promote cancer cell survival include those targeting the FERM domain (G36D, S47N, and R 4 25H), JH2 domain (V731I) and kinase domain (E957D and R 1However, the study also found that the kinase function of TYK2 is required for the enhanced survival of cancer cells, as TYK2 enzymes with kinase-inactivating mutations (M978Y or M978F) in addition to the activating mutation (E957D) resulted in transformation failure.

[0012] Therefore, selective inhibition of TYK2 is considered a suitable target for the treatment of patients with IL-10 and / or BCL2-addicted 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-β (Aβ) peptides. Reduced TYK2 phosphorylation of STAT3 after Aβ administration resulted in reduced neuronal cell death, while increased STAT3 phosphorylation was observed in postmortem brains of Alzheimer's disease patients.

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

[0014] Therefore, compounds that inhibit TYK2 activity are beneficial, particularly those that are selective for JAK2. Such compounds should produce a pharmacological response that advantageously treats one or more of the conditions described herein without the side effects associated with inhibiting JAK2.

[0015] Therefore, there is a need to provide novel inhibitors with more potent or more favorable pharmaceutically relevant properties, such as selectivity over other JAK kinases, in particular JAK2. Summary of the invention

[0016] Described herein are compounds useful for treating TYK2-mediated diseases. In some embodiments, the TYK2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a transplantation-related disease. In some embodiments, the TYK2-mediated disease is cancer.

[0017] For example, disclosed herein are compounds as shown in Formula I:

[0018]

[0019] or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein:

[0020] Ring A is a 6,5- or 6,6-fused bicyclic heteroaryl containing two, three or four ring nitrogens;

[0021] R A Each occurrence is independently selected from: hydrogen, halogen, -NR a R b, C1-C6 alkyl and C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy may be optionally substituted by one or more halogens or deuterium;

[0022] Ring B is a 6,5- or 6,6-fused bicyclic heteroaryl containing one, two or three ring nitrogens;

[0023] R B Each occurrence is independently selected from: hydrogen, halogen, -NR a R b , C1-C6 alkyl and C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy may be optionally substituted by one or more halogens or deuterium;

[0024] Y is selected from: O, N(R a ), S(O)w, CH2 and bond;

[0025] Z is selected from: N(R a ) and O;

[0026] R 1 is independently selected at each occurrence from: deuterium, halogen, hydroxyl, -NR a R b , cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl and C1-C6 alkoxy; wherein R 4 May be substituted on available carbons with hydroxyl groups or one or more halogens;

[0027] R 2 and R 3 are each independently selected from: hydrogen, deuterium and C1-C6 alkyl optionally substituted by one or more halogens; or

[0028] R 2 and R 3 Together with the carbon to which they are attached, they may form a C1-C6 cycloalkyl group;

[0029] R a and R b Each occurrence is independently selected from: hydrogen and C1-C6 alkyl, wherein C1-C6 alkyl may be optionally substituted with one or more halogens or deuterium;

[0030] 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.

[0031] Also disclosed herein are compounds represented by Formula III:

[0032]

[0033] or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein:

[0034] Q is N and T is C; or

[0035] Q is C, and T is N;

[0036] wherein Q and T are each a member of a heteroaromatic ring system;

[0037] V is N(R V ), W is N, and X is N; or

[0038] V is N, W is N(R V ), and X is N; or

[0039] V is N, W is N, and X is N (R X );or

[0040] V is N, W is C (R W ), and X is N(R X );or

[0041] V is N(R V ), W is C(R W ), and X is N; or

[0042] V is N(R V ), W is N, and X is C(R X );or

[0043] V is N, W is N (R W ), and C is C(R X );or

[0044] V is C(R V ), W is N(R W ), and X is N; or

[0045] V is C(R V ), W is N, and X is N(R X );or

[0046] V is N, W is C (R W ), and X is C(R X );or

[0047] V is C(R V ), W is C(R W ), and X is N; or

[0048] V is O, W is N, and X is N (R X );or

[0049] V is C(R V ), W is N, and X is O;

[0050] wherein V, W and X are each a member of a heteroaromatic ring system;

[0051] Y is selected from: O, N(R a ), S(O)w, CH2 and bond;

[0052] R V , R W and R X Each is independently selected from: hydrogen and C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted by one or more substituents, each of which is independently selected from: deuterium, halogen and hydroxyl;

[0053] R 1 is hydrogen or C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted by one or more halogens or deuterium;

[0054] R 2 and R 3 are each independently selected from: hydrogen, deuterium and C1-C6 alkyl which may be optionally substituted with one or more halogens; or

[0055] R 2 and R 3 Together with the carbon to which they are attached, they may form a C3-C6 cycloalkyl group;

[0056] R 4 Each occurrence is independently selected from: deuterium, halogen, hydroxyl, -NR a R b , cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl and C1-C6 alkoxy; wherein R 4 May be substituted on available carbons with hydroxyl groups or one or more halogens;

[0057] R 5 and R 6 are each independently selected from: hydrogen, deuterium and C1-C6 alkyl optionally substituted by one or more halogens; or

[0058] R 5 and R 6 Together with the carbon to which they are attached, they may form a C3-C6 cycloalkyl group;

[0059] R a and R b is independently selected at each occurrence from: hydrogen and C1-C6 alkyl, wherein C1-C6 alkyl may be optionally substituted with one or more deuterium;

[0060] 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.

[0061] Also disclosed herein are compounds represented by Formula IV:

[0062]

[0063] or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein:

[0064] Q is N and T is C; or

[0065] Q is C, and T is N;

[0066] wherein Q and T are each a member of a heteroaromatic ring system;

[0067] V is N(R V ), W is N, and X is N; or

[0068] V is N, W is N (R V ), and X is N; or

[0069] V is N, W is N, and X is N (R X );or

[0070] V is N, W is C (R W ), and X is N(R X );or

[0071] V is N(R V ), W is C(R W ), and X is N; or

[0072] V is N(R V ), W is N, and X is C(R X );or

[0073] V is N, W is N (R W ), and C is C(R X );or

[0074] V is C(R V ), W is N(R W ), and X is N; or

[0075] V is C(R V ), W is N, and X is N(R X );or

[0076] V is N, W is C (R W ), and X is C(R X );or

[0077] V is C(R V ), W is C(R W ), and X is N; or

[0078] V is O, W is N, and X is N (R X );or

[0079] V is C(R V ), W is N, and X is O;

[0080] wherein V, W and X are each a member of a heteroaromatic ring system;

[0081] Y is selected from: O, N(R a ), S(O)w, CH2 and bond;

[0082] R V , R W and R X Each is independently selected from: hydrogen and C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted with one or more substituents, each of which is independently selected from: deuterium, halogen and hydroxyl;

[0083] R 1 is hydrogen or C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted with one or more deuterium;

[0084] R 2 and R 3 are each independently selected from: hydrogen, deuterium and C1-C6 alkyl optionally substituted by one or more halogens; or

[0085] R 2 and R 3 Together with the carbon to which they are attached, they may form a C3-C6 cycloalkyl group;

[0086] R 4 Each occurrence is independently selected from: deuterium, halogen, hydroxyl, -NR a R b , cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl and C1-C6 alkoxy; wherein R 4 May be substituted on available carbons with hydroxyl groups or one or more halogens;

[0087] R a and R b Each occurrence is independently selected from: hydrogen and C1-C6 alkyl optionally substituted with one or more halogens;

[0088] m is 1 or 2; p is 0, 1, 2, 3 or 4; and w is 0, 1 or 2.

[0089] Additionally disclosed herein are tyrosine kinase 2 (TYK2) inhibitory compounds represented by Formula V:

[0090]

[0091] or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein:

[0092] Q is N and T is C; or

[0093] Q is C, and T is N;

[0094] wherein Q and T are each a member of a heteroaromatic ring system;

[0095] V is N(R V ), W is N, and X is N; or

[0096] V is N, W is N (R V ), and X is N; or

[0097] V is N, W is N, and X is N (R X );or

[0098] V is N, W is C (R W ), and X is N(R X );or

[0099] V is N(R V ), W is C(R W ), and X is N; or

[0100] V is N(R V ), W is N, and X is C(R X );or

[0101] V is N, W is N(R W ), and C is C(R X );or

[0102] V is C(R V ), W is N(R W ), and X is N; or

[0103] V is C(R V ), W is N, and X is N(R X );or

[0104] V is N, W is C (R W ), and X is C(R X );or

[0105] V is C(R V ), W is C(R W ), and X is N; or

[0106] V is O, W is N, and X is N (R X );or

[0107] V is C(R V ), W is N, and X is O;

[0108] wherein V, W and X are each a member of a heteroaromatic ring system;

[0109] Z is selected from: N(R a ) and O;

[0110] R V , R W and R X Each is independently selected from: hydrogen and C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted with one or more substituents, each of which is independently selected from: deuterium, halogen and hydroxyl;

[0111] R 1 is hydrogen or C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted with one or more deuterium;

[0112] R 2 and R 3 are each independently selected from: hydrogen, deuterium and C1-C6 alkyl optionally substituted by one or more halogens; or

[0113] R 2 and R 3 Together with the carbon to which they are attached, they may form a C3-C6 cycloalkyl group;

[0114] R 4 Each occurrence is independently selected from: deuterium, halogen, hydroxyl, -NR a R b , cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl and C1-C6 alkoxy; wherein R 4 May be substituted on available carbons with hydroxyl groups or one or more halogens;

[0115] R a and R b is independently selected at each occurrence from: hydrogen and C1-C6 alkyl, wherein C1-C6 alkyl may be optionally substituted with one or more deuterium;

[0116] m is 1 or 2; and p is 0, 1, 2, 3 or 4.

[0117] Also disclosed herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, and a pharmaceutically acceptable excipient.

[0118] Also disclosed herein is a method of inhibiting a TYK2 enzyme in a patient or a biological sample, comprising contacting the patient or the biological sample with a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0119] Also disclosed herein is a method for treating a TYK2-mediated disease, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof to a patient in need thereof. In some embodiments, the TYK2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a nervous system disease, or a transplant-related disease. In some embodiments, the disease is associated with type I interferon, IL-10, IL-12, or IL-23 signal transduction. DETAILED DESCRIPTION OF THE INVENTION

[0121] The features and other details of the present disclosure will now be described in more detail. Before further describing the present disclosure, some terms used in the specification, examples, and appended claims are collected here. These definitions should be understood in conjunction with the remainder of the present disclosure and are understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art.

[0122] definition

[0123] As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, reference to "the cell" includes reference to one or more cells (or cells) known to those skilled in the art and equivalents thereof, and so on. When ranges are used herein to describe physical properties (e.g., molecular weight) or chemical properties (e.g., chemical formula), all combinations and subcombinations of ranges and specific embodiments thereof are intended to be included. When referring to a number or a numerical range, the term "about" means that the number or numerical range referred to is an approximation within experimental variation (or within statistical experimental error), and thus, in some cases, the number or numerical range will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms, such as "comprise(s)" or "having" or "including") is not intended to exclude that certain other embodiments, e.g., embodiments of any composition of matter, composition, method or process, etc. described herein "consist of" or "consist essentially of" the recited features.

[0124] As used in the specification and the appended claims, the following terms have the following meanings unless otherwise specified.

[0125] "Oxo" refers to =0.

[0126] "Alkyl" refers to an optionally substituted straight chain or optionally substituted branched 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, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Numerical ranges such as "C1-C6 alkyl" appearing herein indicate 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, but the definition also encompasses the term "alkyl" without specifying a numerical range. In some embodiments, the alkyl group is C1-C6. 10 Alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl or C1 alkyl. Unless otherwise specifically stated in this specification, alkyl can be optionally substituted by a substituent such as selected from the group consisting of oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl can be optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, alkyl can be optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, alkyl can be optionally substituted by halogen.

[0127] "Alkenyl" refers to an optionally substituted straight chain or optionally substituted branched hydrocarbon monoradical having one or more carbon-carbon double bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The group can be in a cis or trans conformation about the double bond, and should be understood to include two isomers. Examples include, but are not limited to: vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. The numerical ranges appearing herein, such as "C2-C6 alkenyl", indicate that the alkenyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the term "alkenyl" for which no numerical range is specified is also encompassed by this definition. In some embodiments, alkenyl is C2-C6. 10Alkenyl, C2-C9 alkenyl, C2-C8 alkenyl, C2-C7 alkenyl, C2-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl or C2 alkenyl.Unless otherwise specifically stated in this specification, alkenyl can be optionally replaced by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkenyl can be optionally replaced by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, alkenyl can be optionally replaced by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, alkenyl can be optionally replaced by halogen.

[0128] "Alkynyl" refers to an optionally substituted straight chain or optionally substituted branched hydrocarbon monoradical having one or more carbon-carbon triple bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Numerical ranges appearing herein, such as "C2-C6 alkynyl", indicate that the alkynyl group may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the definition also encompasses the term "alkynyl" without specifying a numerical range. In some embodiments, the alkynyl group is C2-C6. 10 Alkynyl, C2-C9 alkynyl, C2-C8 alkynyl, C2-C7 alkynyl, C2-C6 alkynyl, C2-C5 alkynyl, C2-C4 alkynyl, C2-C3 alkynyl or C2 alkynyl.Unless otherwise specifically stated in this specification, alkynyl can be optionally replaced by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkynyl is optionally replaced by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, alkynyl can be optionally replaced by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, alkynyl can be optionally replaced by halogen.

[0129] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specifically stated in this specification, alkylene may be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene may be optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, alkylene may be optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, alkylene may be optionally substituted by halogen.

[0130] "Alkoxy" refers to a group of formula -oxyalkyl, wherein alkyl is as defined above. Unless otherwise specifically stated in this specification, alkoxy may be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkoxy may be optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, alkoxy may be optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, alkoxy may be optionally substituted by halogen.

[0131] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amino groups. In some embodiments, the alkyl group is substituted with one amino group. In some embodiments, the alkyl group is substituted with one, two, or three amino groups. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0132] "Aryl" refers to a group derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. Aryl can be a monocyclic, bicyclic, tricyclic or tetracyclic system, which can include a fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is combined by an aromatic ring atom) or a bridged ring system. In some embodiments, aryl is a 6 to 10 yuan aryl. In some embodiments, aryl is a 6 yuan aryl. Aryl includes but is not limited to: aryl derived from anthracene, naphthyl, phenanthrenyl, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, asymmetric-indacene, symmetric-indacene, indane, indene, naphthalene, phenanthren, phenanthren, pyrene and triphenylene hydrocarbon ring system. In some embodiments, aryl is phenyl. Unless otherwise clearly stated in this specification, aryl can be optionally substituted by, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, aryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, aryl can be optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, aryl can be optionally substituted by halogen.

[0133] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused (when fused to an aryl or heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having 3 to 15 carbon atoms (C3-C 15 cycloalkyl), cycloalkyl having 3 to 10 carbon atoms (C3-C 10In some embodiments, the cycloalkyl group is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl group is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocyclic rings 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, bicyclo[3.3.2]decane and 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unless otherwise expressly stated in the specification, cycloalkyl may be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, cycloalkyl may be optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, cycloalkyl may be optionally substituted with halogen.

[0134] "Deuterated alkyl" refers to an alkyl group as defined above that is substituted with one or more deuterium atoms. In some embodiments, the alkyl group is substituted with one deuterium atom. In some embodiments, the alkyl group is substituted with one, two or three deuterium atoms. In some embodiments, the alkyl group is substituted with one, two, three, four, five or six deuterium atoms. Deuterated alkyl groups include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D or CH2CHD2. In some embodiments, the deuterated alkyl group is CD3.

[0135] "Haloalkyl" refers to an alkyl group as defined above that is substituted with one or more halogen atoms. In some embodiments, the alkyl group is substituted with one, two, or three halogen atoms. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six halogen atoms. Haloalkyl groups include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. In some embodiments, haloalkyl is trifluoromethyl.

[0136] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0137] "Assorted alkyl" refers to an atom in which one or more skeleton atoms are selected from carbon, such as oxygen, nitrogen (such as-NH-,-N (alkyl)-), sulfur, or a combination thereof. Assorted alkyl is connected to the rest of the molecule on the carbon atom of the assorted alkyl. On the one hand, assorted alkyl is C1-C6 assorted alkyl, wherein assorted alkyl is composed of 1 to 6 carbon atoms and one or more atoms (such as oxygen, nitrogen (such as-NH-,-N (alkyl)-), sulfur or a combination thereof) other than carbon, wherein the assorted alkyl is connected to the rest of the molecule at the carbon atom of the assorted alkyl. The example of such assorted alkyl is, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3 or -CH(CH3)OCH3. Unless otherwise specifically stated in this specification, assorted alkyl may be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyl may be optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyl may be optionally substituted with halogen.

[0138] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0139] "Heterocycloalkyl" refers to a 3-24 membered partially or fully saturated cyclic group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur. In some embodiments, the heterocycloalkyl contains 1 or 2 heteroatoms selected from nitrogen and oxygen. Unless otherwise expressly stated in this specification, the heterocycloalkyl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused (when fused with an aromatic ring or a heteroaromatic ring, the heterocycloalkyl is connected by a non-aromatic ring atom) or a bridged ring system; the nitrogen, carbon or sulfur atoms in the heterocycloalkyl can be optionally oxidized; the nitrogen atom can be optionally quaternized. Representative heterocycloalkyls include, but are not limited to: heterocycloalkyls (C2-C4) having 2 to 15 carbon atoms; 15 Heterocycloalkyl), heterocycloalkyl of 2 to 10 carbon atoms (C2-C 10In some embodiments, the heterocycloalkyl group is a 3- to 6-membered heterocycloalkyl group. In some embodiments, the cycloalkyl group is a 5- to 6-membered heterocycloalkyl group. Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]disilathianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidine The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. It should be understood that when referring to the number of carbon atoms of heterocycloalkyl, the number of carbon atoms of heterocycloalkyl is different from the total number of atoms (including heteroatoms) constituting the heterocycloalkyl (i.e., the backbone atoms of the heterocycloalkyl ring). Unless otherwise clearly stated in this specification, heterocycloalkyl is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heterocycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, heterocycloalkyl can be optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, heterocycloalkyl can be optionally substituted by halogen.

[0140] "Heteroaryl" refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. The heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, and can include a fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl group is bound by an aromatic ring atom) or a bridged ring system; the nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothienyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, isothiazolyl , imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridyl, 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, quinuclidine, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated in this specification, heteroaryl can be optionally substituted by, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, heteroaryl can be optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, heteroaryl can be optionally substituted by halogen.

[0141] The terms "treatment", "prevention", "improvement", and "inhibition" used herein and the words derived therefrom do not necessarily mean 100% or complete treatment, prevention, improvement or inhibition. On the contrary, there are different degrees of treatment, prevention, improvement and inhibition, and those of ordinary skill in the art believe that these treatments, preventions, improvements and inhibitions have potential benefits or therapeutic effects. In this regard, the disclosed methods can provide any level of treatment, prevention, improvement or inhibition of any number of diseases in mammals. For example, the disease (including its symptoms or conditions) can be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20% or about 10%. In addition, the treatment, prevention, improvement or inhibition provided by the methods disclosed herein can include one or more conditions or symptoms of the disease, such as cancer or inflammatory diseases, for example. In addition, for the purposes of this article, "treatment", "prevention", "improvement" or "inhibition" covers delaying the onset of a disease or its symptoms or conditions.

[0142] The term "effective amount" or "therapeutically effective amount" as used herein refers to the administration of a sufficient amount of a compound disclosed herein that will alleviate to some extent one or more 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 biological system changes. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms. In some embodiments, techniques such as dose escalation studies are used to determine the appropriate "effective" amount in any individual case.

[0143] As used herein, the term "TYK2-mediated" disorder, disease and / or condition refers to any disease or other deleterious condition in which TYK2 or a mutant thereof is known to play a role. Thus, another embodiment relates to treating or lessening the severity of one or more diseases in which TYK2 or a mutant thereof is known to play a role. Such TYK2-mediated diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, and transplantation-related diseases.

[0144] Compound

[0145] Described herein are compounds useful for treating TYK2-mediated diseases. In some embodiments, the TYK2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a transplantation-related disease. In some embodiments, the TYK2-mediated disease is cancer.

[0146] For example, disclosed herein are compounds represented by Formula I:

[0147]

[0148] or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein:

[0149] Ring A is a 6,5- or 6,6-fused bicyclic heteroaryl containing two, three or four ring nitrogens;

[0150] R A Each occurrence is independently selected from: hydrogen, halogen, -NR a R b , C1-C6 alkyl and C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy may be optionally substituted by one or more halogens or deuterium;

[0151] Ring B is a 6,5- or 6,6-fused bicyclic heteroaryl containing one, two or three ring nitrogens;

[0152] R B Each occurrence is independently selected from: hydrogen, halogen, -NR a R b , C1-C6 alkyl and C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy may be optionally substituted by one or more halogens or deuterium;

[0153] Y is selected from: O, N(R a )、S(O) w , CH2 and bond;

[0154] Z is selected from: N(R a ) and O;

[0155] R 1 Each occurrence is independently selected from: deuterium, halogen, hydroxyl, -NR a R b , cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl and C1-C6 alkoxy; wherein R 4 May be substituted on available carbons with hydroxyl groups or one or more halogens;

[0156] R 2 and R 3 are each independently selected from: hydrogen, deuterium and C1-C6 alkyl which may be optionally substituted with one or more halogens; or

[0157] R 2 and R 3 Together with the carbon to which they are attached they form a C3-C6 cycloalkyl group;

[0158] R a and R bis independently selected at each occurrence from: hydrogen and C1-C6 alkyl, wherein C1-C6 alkyl may be optionally substituted with one or more halogens or deuterium;

[0159] 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.

[0160] In some embodiments, Ring A is represented by:

[0161] in:

[0162] Q is N and T is C; or Q is C and T is N; and

[0163] R A Selected from: -N(H)CH3, -NH2, hydrogen and -OCH3;

[0164] wherein * represents the point of attachment to the -NH- group in formula I.

[0165] For example, in certain embodiments, Ring A is selected from:

[0166]

[0167] In other embodiments, Ring A is represented by:

[0168]

[0169] Wherein: T is N or CH;

[0170] R A1 is selected from: -N(H)CH3, -NH2, hydrogen and -OCH3; and R A2 Selected from: hydrogen and -CH3;

[0171] wherein * represents the point of attachment to the -NH- group in formula I.

[0172] For example, in certain embodiments, Ring A is selected from:

[0173]

[0174] In a further embodiment, Ring B is represented by:

[0175] in

[0176] V is N(R V ), W is N, and X is N; or

[0177] V is N, W is N (R V ), and X is N; or

[0178] V is N, W is N, and X is N (R X );or

[0179] V is N, W is C (R W ), and X is N(R X );or

[0180] V is N(R V ), W is C(R W ), and X is N; or

[0181] V is N(R V ), W is N, and X is C(R X );or

[0182] V is N, W is N(R W ), and C is C(R X );or

[0183] V is C(R V ), W is N(R W ), and X is N; or

[0184] V is C(R V ), W is N, and X is N(R X );or

[0185] V is N, W is C (R W ), and X is C(R X );or

[0186] V is C(R V ), W is C(R W ), and X is N; or

[0187] V is O, W is N, and X is N (R X );or

[0188] V is C(R V ), W is N, and X is O; or

[0189] V is O, W is C (R W ), and X is N; or

[0190] V is N, W is C (R W ), and X is O; and

[0191] R V , R W and R X Each is independently selected from: hydrogen and C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted by one or more substituents, and the substituents are each independently selected from: deuterium, halogen and hydroxyl;

[0192] wherein * represents the point of attachment to the -NH- group in formula I.

[0193] For example, in certain embodiments, Ring B is represented by:

[0194]

[0195] Where R V , R W and R X Each is independently selected from: hydrogen, -CH3 and -CD3.

[0196] In other embodiments, B is represented by:

[0197]

[0198] Where R V , R W and R X Each is independently selected from: hydrogen, -CH3 and -CD3.

[0199] In still further embodiments, Ring B is represented by:

[0200] in:

[0201] U, V, W, X, Y and Z are each independently selected from: N and C (R B ); wherein one or two of U, V, W, X, Y and Z are N; and

[0202] R B Each occurrence is independently selected from: hydrogen, halogen, C1-C3 alkyl and C1-C3 alkoxy;

[0203] wherein * represents the point of attachment to the -NH- group in formula I.

[0204] For example, in certain embodiments, Ring B is selected from:

[0205]

[0206] Where R B Selected from: hydrogen, -CH3 and -OCH3.

[0207] In other embodiments, Ring B is selected from: wherein * represents the point of attachment to the -NH- group in formula I.

[0208] In other embodiments, the compound of Formula I may be represented by Formula II:

[0209]

[0210] In some embodiments, the compounds disclosed herein are represented by:

[0211]

[0212] In other embodiments, the compounds disclosed herein are represented by:

[0213]

[0214] In other embodiments, the compounds disclosed herein are represented by:

[0215]

[0216] In a further embodiment, the compounds disclosed herein are represented by:

[0217]

[0218] In some embodiments, the compounds disclosed herein are represented by:

[0219]

[0220] In other embodiments, the compounds disclosed herein are represented by:

[0221]

[0222]

[0223] In some embodiments, R X , R W and R V Each is C1-C6 alkyl, which is optionally substituted with one or more deuterium. For example, in certain embodiments, R X , R W and R V Each is independently selected from: -CH3 and -CD3.

[0224] In certain 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 the group consisting of: O, NH, and NCH3. In other embodiments, Z is NH.

[0225] In some embodiments, R 2 and R 3 Each independently selected from: hydrogen, deuterium, -CH3 and -CF3; or R 2 and R 3 Together with the carbon to which they are attached they form a cyclopropyl group.

[0226] In some embodiments, m is 1. In other embodiments, m is 2. In other embodiments, n is 0. In further embodiments, n is 1. In certain embodiments, p is 1 and R 4 It is hydroxyl or -CH2OH.

[0227] Also disclosed herein are compounds represented by Formula III:

[0228]

[0229] or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein:

[0230] Q is N and T is C; or Q is C and T is N;

[0231] wherein Q and T are each a member of a heteroaromatic ring system;

[0232] V is N(R V ), W is N, and X is N; or

[0233] V is N, W is N (R V ), and X is N; or

[0234] V is N, W is N, and X is N (R X );or

[0235] V is N, W is C (R W ), and X is N(R X );or

[0236] V is N(R V ), W is C(R W ), and X is N; or

[0237] V is N(R V ), W is N, and X is C(R X );or

[0238] V is N, W is N (R W ), and C is C(R X );or

[0239] V is C(R V ), W is N(R W ), and X is N; or

[0240] V is C(R V ), W is N, and X is N(R X );or

[0241] V is N, W is C (R W ), and X is C(R X );or

[0242] V is C(R V ), W is C(R W ), and X is N; or

[0243] V is O, W is N, and X is N (R X );or

[0244] V is C(R V ), W is N, and X is O;

[0245] wherein V, W and X are each a member of a heteroaromatic ring system;

[0246] Y is selected from: O, N(R a )、S(O) w , CH2 and bond;

[0247] R V , R W and R X Each is independently selected from: hydrogen and C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted with one or more substituents, each of which is independently selected from: deuterium, halogen and hydroxyl;

[0248] R 1 is hydrogen or C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted by one or more halogens or deuterium;

[0249] R 2 and R 3 are each independently selected from: hydrogen, deuterium and C1-C6 alkyl which may be optionally substituted with one or more halogens; or

[0250] R 2 and R 3 Together with the carbon to which they are attached, they may form a C3-C6 cycloalkyl group;

[0251] R 4 Each occurrence is independently selected from: deuterium, halogen, hydroxyl, -NR a R b , cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl and C1-C6 alkoxy; wherein R 4 May be substituted on available carbons with hydroxyl groups or one or more halogens;

[0252] R 5 and R 6 are each independently selected from: hydrogen, deuterium and C1-C6 alkyl which may be optionally substituted with one or more halogens; or

[0253] R 5 and R 6Can be linked together with the carbon to which they are attached to form a C3-C6 cycloalkyl group;

[0254] R a and R b is independently selected at each occurrence from: hydrogen and C1-C6 alkyl, wherein C1-C6 alkyl may be optionally substituted with one or more deuterium;

[0255] 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.

[0256] In some embodiments, the compounds disclosed herein are represented by:

[0257]

[0258] In other embodiments, the compounds disclosed herein are represented by:

[0259]

[0260] In other embodiments, the compounds disclosed herein are represented by:

[0261]

[0262] In a further embodiment, the compounds disclosed herein are represented by:

[0263]

[0264]

[0265] In some embodiments, the compounds disclosed herein are represented by:

[0266]

[0267] In other embodiments, the compounds disclosed herein are represented by:

[0268]

[0269] In some embodiments, R X , R W and R V Each is a C1-C6 alkyl group optionally substituted with one or more deuterium. For example, in certain embodiments, R X , R W and R V Each is independently selected from: -CH3 and -CD3. In other embodiments, Y is O.

[0270] In a further embodiment, R 1is a C1-C6 alkyl group optionally substituted with one or more deuteriums. For example, in certain embodiments, R 1 Selected from: -CH3 and -CD3.

[0271] In other embodiments, R 2 and R 3 Each independently selected from: hydrogen, deuterium, -CH3 and -CF3; or R 2 and R 3 Together with the carbon to which they are attached they form a cyclopropyl group.

[0272] In some embodiments, R 5 and R 6 Each is independently selected from: hydrogen, deuterium, -CH3 and -CF3.

[0273] In some embodiments, m is 1. In other embodiments, m is 2. In other embodiments, n is 0. In further embodiments, n is 1. In certain embodiments, p is 1, and R 4 It is hydroxyl or -CH2OH.

[0274] Further disclosed herein are compounds represented by Formula IV:

[0275]

[0276] or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein:

[0277] Q is N and T is C; or Q is C and T is N;

[0278] wherein Q and T are each a member of a heteroaromatic ring system;

[0279] V is N(R V ), W is N, and X is N; or

[0280] V is N, W is N(R V ), and X is N; or

[0281] V is N, W is N, and X is N (R X );or

[0282] V is N, W is C (R W ), and X is N(R X );or

[0283] V is N(R V ), W is C(R W ), and X is N; or

[0284] V is N(R V ), W is N, and X is C(R X);or

[0285] V is N, W is N(R W ), and C is C(R X );or

[0286] V is C(R V ), W is N(R W ), and X is N; or

[0287] V is C(R V ), W is N, and X is N(R X );or

[0288] V is N, W is C (R W ), and X is C(R X );or

[0289] V is C(R V ), W is C(R W ), and X is N; or

[0290] V is O, W is N, and X is N (R X );or

[0291] V is C(R V ), W is N, and X is O;

[0292] wherein V, W and X are each a member of a heteroaromatic ring system;

[0293] Y is selected from: O, N(R a )、S(O) w , CH2 and bond;

[0294] R V , R W and R X Each is independently selected from: hydrogen and C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted with one or more substituents, each of which is independently selected from: deuterium, halogen and hydroxyl;

[0295] R 1 is hydrogen or C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted with one or more deuterium;

[0296] R 2 and R 3 are each independently selected from: hydrogen, deuterium and C1-C6 alkyl which may be optionally substituted with one or more halogens; or

[0297] R 2 and R 3 Together with the carbon to which they are attached, they may form a C3-C6 cycloalkyl group;

[0298] R4 Each occurrence is independently selected from: deuterium, halogen, hydroxyl, -NR a R b , cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl and C1-C6 alkoxy; wherein R 4 May be substituted on available carbons with hydroxyl groups or one or more halogens;

[0299] R a and R b Each occurrence is independently selected from: hydrogen and C1-C6 alkyl optionally substituted with one or more halogens;

[0300] m is 1 or 2; p is 0, 1, 2, 3 or 4; and w is 0, 1 or 2.

[0301] In some embodiments, the compounds disclosed herein are represented by:

[0302]

[0303] In other embodiments, the compounds disclosed herein are represented by:

[0304]

[0305] In other embodiments, the compounds disclosed herein are represented by:

[0306]

[0307] In a further embodiment, the compounds disclosed herein are represented by:

[0308]

[0309] In some embodiments, the compounds disclosed herein are represented by:

[0310]

[0311] In other embodiments, the compounds disclosed herein are represented by:

[0312]

[0313] In some embodiments, R X , R W and R V Each is a C1-C6 alkyl group optionally substituted with one or more deuterium. For example, in certain embodiments, R X , R W and R V Each is independently selected from: -CH3 and -CD3. In other embodiments, Y is O.

[0314] In a further embodiment, R 1 is a C1-C6 alkyl group optionally substituted with one or more deuteriums. For example, in certain embodiments, R 1 Selected from: -CH3 and -CD3.

[0315] In other embodiments, R 2 and R 3 Each independently selected from: hydrogen, deuterium, -CH3 and -CF3; or R 2 and R 3 Together with the carbon to which they are attached they form a cyclopropyl group.

[0316] In some embodiments, m is 1. In other embodiments, m is 2. In certain embodiments, p is 1, and R 4 It is hydroxyl or -CH2OH.

[0317] Also disclosed herein are compounds represented by Formula V:

[0318]

[0319] or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein:

[0320] Q is N and T is C; or

[0321] Q is C, and T is N;

[0322] wherein Q and T are each a member of a heteroaromatic ring system;

[0323] V is N(R V ), W is N, and X is N; or

[0324] V is N, W is N (R V ), and X is N; or

[0325] V is N, W is N, and X is N (R X );or

[0326] V is N, W is C (R W ), and X is N(R X );or

[0327] V is N(R V ), W is C(R W ), and X is N; or

[0328] V is N(R V ), W is N, and X is C(R X );or

[0329] V is N, W is N (RW ), and C is C(R X );or

[0330] V is C(R V ), W is N(R W ), and X is N; or

[0331] V is C(R V ), W is N, and X is N(R X );or

[0332] V is N, W is C (R W ), and X is C(R X );or

[0333] V is C(R V ), W is C(R W ), and X is N; or

[0334] V is O, W is N, and X is N (R X );or

[0335] V is C(R V ), W is N, and X is O;

[0336] wherein V, W and X are each a member of a heteroaromatic ring system;

[0337] Z is selected from: N(R a ) and O;

[0338] R V , R W and R X Each is independently selected from: hydrogen and C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted with one or more substituents, each of which is independently selected from: deuterium, halogen and hydroxyl;

[0339] R 1 is hydrogen or C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted with one or more deuterium;

[0340] R 2 and R 3 are each independently selected from: hydrogen, deuterium and C1-C6 alkyl optionally substituted by one or more halogens; or

[0341] R 2 and R 3 Can be linked together with the carbon to which they are attached to form a C3-C6 cycloalkyl group;

[0342] R 4 Each occurrence is independently selected from: deuterium, halogen, hydroxyl, -NR a R b, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl and C1-C6 alkoxy; wherein R 4 May be substituted on available carbons with hydroxyl groups or one or more halogens;

[0343] R a and R b is independently selected at each occurrence from: hydrogen and C1-C6 alkyl, wherein C1-C6 alkyl may be optionally substituted with one or more deuterium;

[0344] m is 1 or 2; and p is 0, 1, 2, 3 or 4.

[0345] In some embodiments, the compounds disclosed herein are represented by:

[0346]

[0347] In other embodiments, the compounds disclosed herein are represented by:

[0348]

[0349]

[0350] In other embodiments, the compounds disclosed herein are represented by:

[0351] In a further embodiment, the compounds disclosed herein are represented by:

[0352] In some embodiments, the compounds disclosed herein are represented by:

[0353]

[0354] In other embodiments, the compounds disclosed herein are represented by:

[0355]

[0356] In some embodiments, R X , R W and R V Each is a C1-C6 alkyl group optionally substituted with one or more deuterium. For example, in certain embodiments, R X , R W and R V Each is independently selected from: -CH3 and -CD3. In other embodiments, Z is NH.

[0357] In a further embodiment, R 1is a C1-C6 alkyl group optionally substituted with one or more deuteriums. For example, in certain embodiments, R 1 Selected from: -CH3 and -CD3.

[0358] In other embodiments, R 2 and R 3 Each independently selected from: hydrogen, deuterium, -CH3 and -CF3; or R 2 and R 3 Together with the carbon to which they are attached they form a cyclopropyl group.

[0359] In some embodiments, m is 1. In other embodiments, m is 2. In certain embodiments, p is 1, and R 4 It is hydroxyl or -CH2OH.

[0360] Also disclosed herein is a compound selected from any of the compounds shown in Table 1, or a pharmaceutically acceptable salt and / or stereoisomer thereof.

[0361] Table 1.

[0362]

[0363]

[0364]

[0365]

[0366]

[0367] Further forms of the compounds disclosed herein

[0368] Isomers / stereoisomers

[0369] In some embodiments, the compounds described herein exist in the form of geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis, trans, cis coordination (syn), trans coordination (anti), entgegen (E) and zusammen (Z) isomers, and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, and each center is present in the R configuration or S configuration. The compounds described herein include all diastereoisomers, enantiomers and epimer forms, and their corresponding mixtures. In other embodiments of the compounds and methods provided herein, the enantiomers and / or mixtures of diastereomers produced by a single preparation step, combination or mutual conversion can be used for the applications described herein. In some embodiments, by reacting the racemic mixture of the compound with an optically active resolving agent, a pair of diastereoisomer compounds are formed, diastereomers are separated, and optically pure enantiomers are recovered, and the compounds described herein are prepared as their individual stereoisomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.), and these differences are used to separate. In some embodiments, diastereomers are separated by chiral chromatography, or preferably by separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomer is then recovered together with a resolving agent.

[0370] Labeled compounds

[0371] In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds as pharmaceutical compositions. Therefore, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to the compounds described herein, but one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically 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 chlorine, such as respectively 2 H. 3 H. 13 C. 14 C. l5 N. 18 O. 17 O. 31 P. 32 P.35 S. 18 F and 36 The compounds described herein and their pharmaceutically acceptable salts, solvates or stereoisomers (which contain the aforementioned isotopes and / or other isotopes of other atoms) are within the scope of the present disclosure. Certain isotopically labeled compounds, for example, compounds incorporating radioactive isotopes (such as 3 H and 14 C) compounds can be used for drug and / or substrate tissue distribution analysis. 3 H) and carbon-14 isotopes (i.e. 14 C) is particularly favored due to its ease of preparation and detectability. In addition, heavy isotopes (such as deuterium, i.e. 2 H) substitution may produce certain therapeutic advantages due to higher metabolic stability, such as increasing half-life in vivo or reducing dosage requirements. In some embodiments, isotopically labeled compounds or pharmaceutically acceptable salts, solvates or stereoisomers thereof are prepared by any suitable method.

[0372] 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.

[0373] Pharmaceutically acceptable salts

[0374] In some embodiments, the compounds described herein exist in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0375] In some embodiments, the compounds described herein have acidic or basic groups and can therefore react with a variety of inorganic or organic bases, as well as inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting the purified compound in free form with a suitable acid or base and isolating the salt thus formed.

[0376] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with mineral, organic acids or inorganic bases, such salts include acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, hexanoate, octanoate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undeconate, and xylenesulfonate.

[0377] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts, which are formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including but not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, Benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethylsulfonic 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.

[0378] In some embodiments, the compounds described herein containing free acid groups are reacted with a suitable base (e.g., a pharmaceutically acceptable hydroxide, carbonate, bicarbonate, or sulfate of a metal cation), with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali metal salts or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium, aluminum salts, and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 Alkyl)4, etc.

[0379] Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water-soluble or oil-soluble or dispersible products are obtained by such quaternization.

[0380] Solvate

[0381] In some embodiments, the compounds described herein exist in the form of solvates. The present disclosure provides methods for treating diseases by administering such solvates. The present disclosure also provides methods for treating diseases by administering such solvates as pharmaceutical compositions.

[0382] Solvates contain stoichiometric or non-stoichiometric amounts of solvents, such as water, ethanol, and the like. When the solvent is water, hydrates are formed; or when the solvent is alcohol, ethanolates are formed. Solvates of the compounds described herein can be conveniently prepared or formed in the methods described herein. In addition, the compounds provided herein can exist in unsolvated forms as well as solvated forms. In general, for the purposes of the compounds and methods provided herein, the solvated forms are considered equivalent to the unsolvated forms.

[0383] Tautomer

[0384] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the molecular formulas described herein. Tautomers are compounds that are interconverted by the migration of hydrogen atoms, accompanied by the conversion of single bonds and adjacent double bonds. In the bonding arrangements where tautomerism is possible, chemical equilibrium will be established between tautomers. All tautomeric forms of the compounds described herein are contemplated. The exact ratio of tautomers depends on a variety of factors, including temperature, solvent, and pH.

[0385] Pharmaceutical composition

[0386] In certain embodiments, the compounds described herein are administered as pure chemicals. In some embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st The chosen route of administration is selected based on the route of administration described in Pharmacopoeia (2005) and standard pharmaceutical practice.

[0387] Therefore, provided herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0388] In certain embodiments, the compounds provided herein are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthesis byproducts produced during one or more steps of the synthetic method.

[0389] The pharmaceutical composition is applied in a manner suitable for the disease to be treated (or prevented). Appropriate dosage and suitable duration and frequency of application will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient and the method of administration. In general, appropriate dosage and treatment regimen provide the composition in an amount sufficient to provide treatment and / or prevention benefits (e.g., improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival periods, or to reduce 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, body weight or blood volume.

[0390] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal, epidural and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical application or ocular administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated into tablets, pills, capsules, liquids, inhalants, nasal sprays, suppositories, suspensions, gels, colloids, dispersions, suspensions, solutions, emulsions, ointments, lotions, eye drops or ear drops. In some embodiments, the pharmaceutical composition is formulated as tablets.

[0391] Suitable dosages and administration regimens are determined by conventional range-finding techniques known to those of ordinary skill in the art. In general, treatment begins with a smaller dose that is less than the optimal dose of the compound disclosed herein. Thereafter, the dose is increased in small increments until the best effect is achieved under the current circumstances. In some embodiments, the method involves administering about 0.1 μg to about 50 mg of at least one compound described herein per kilogram of subject body weight. For a patient weighing 70 kilograms, a dose of about 10 μg to about 200 mg of the compound disclosed herein is more commonly used, depending on the subject's physiological response.

[0392] By way of example only, the dosage of a compound described herein for use in the methods of treating a disease described herein is 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 dosage of a compound described herein for use in the methods is from about 1 to about 1000 mg / kg body weight of the individual being treated per day, for example, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.

[0393] Treatment

[0394] The compounds disclosed herein, or pharmaceutically acceptable salts, solvates or stereoisomers thereof, can be used to inhibit the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by the compounds and methods is TYK2.

[0395] Provided herein are compounds that are inhibitors of TYK2 and are therefore useful in treating one or more diseases associated with the activity of TYK2 or a mutant thereof.

[0396] Provided herein are methods for treating a disease or condition, wherein the disease or condition is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a transplantation-related disease, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0397] In some embodiments, the disease or condition is an autoimmune disease. In some embodiments, the disease or condition 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.

[0398] In some embodiments, the disease or disorder is an inflammatory disease. In some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, inflammatory bowel disease.

[0399] In some embodiments, the disease or condition is a proliferative disease. In some embodiments, the proliferative disease is cancer. In some embodiments, the disease or condition is a proliferative disease. In some embodiments, the proliferative disease is a hematological cancer. In some embodiments, the proliferative disease is a leukemia. In some embodiments, the leukemia is a T-cell leukemia. In some embodiments, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disease is polycythemia vera, myelofibrosis, primary or essential thrombocythemia.

[0400] In some embodiments, the disease or condition is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon syndrome, or type 1 diabetes.

[0401] In some embodiments, the disease or disorder is a neurological disease. In some embodiments, the neurological disease is Alzheimer's disease.

[0402] In some embodiments, the proliferative disease is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation in the FERM domain, the JH2 domain, or the kinase domain. In some embodiments, the activating mutation in TYK2 is selected from the group consisting of: G36D, S47N, R425H, V731I, E957D, and R1027H.

[0403] In some embodiments, the disease or disorder is associated with transplantation. In some embodiments, the disease or disorder associated with transplantation is transplant rejection or graft-versus-host disease.

[0404] In some embodiments, the disease or condition is associated with type I interferon, IL-10, IL-12 or IL-23 signal transduction. In some embodiments, the disease or condition is associated with type I interferon signal transduction. In some embodiments, the disease or condition is associated with IL-10 signal transduction. In some embodiments, the disease or condition is associated with IL-12 signal transduction. In some embodiments, the disease or condition is associated with IL-23 signal transduction.

[0405] Provided herein are methods of treating inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, pemphigus neoplasticus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0406] Provided herein are methods of treating other diseases or conditions, such as those with an inflammatory component, such as treating ocular diseases and conditions, such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory diseases in which an autoimmune response is involved or which have an autoimmune component or etiology, 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, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcers), colitis and Crohn's disease), irritable bowel syndrome, celiac disease with diarrhea, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine eye disease, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjögren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, periodic syndromes associated with pyrogens, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome, including, for example, idiopathic nephrotic syndrome or minimal change disease), chronic granulomatous disease , endometriosis, leptospirosis nephropathy, glaucoma, retinal diseases, aging, headache, pain, complex regional pain syndrome, cardiomegaly, muscle wasting, metabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic involucral dysplasia, Behcet's disease, incontinence pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic, mild, moderate, severe, bronchitis, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity reactions, anaphylaxis, sinusitis, eye allergies, silica-induced disease, chronic obstructive pulmonary disease (damage reduction, airway inflammation, bronchi airway hyperresponsiveness, remodeling, or disease progression), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis,Hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0407] In some embodiments, the inflammatory disease is acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), chillin-associated periodic syndrome (CAPS), or osteoarthritis.

[0408] 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).

[0409] In some embodiments, the inflammatory disease is Sjögren's syndrome, an allergic disease, osteoarthritis, an ocular condition such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, or a disease affecting the nose such as allergic rhinitis.

[0410] For example, disclosed herein is a method of inhibiting a TYK2 enzyme in a patient or a biological sample, comprising contacting the patient or the biological sample with a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein.

[0411] 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 compound disclosed herein or a pharmaceutical composition disclosed herein. In some embodiments, inhibiting 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.

[0412] Further disclosed herein are TYK2-mediated diseases in patients in need of treatment, comprising administering to the patient a therapeutically effective amount of a disclosed compound or pharmaceutical composition. In some embodiments, the contemplated TYK2-mediated disease can be, for example, an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a disease associated with transplantation. In other embodiments, the contemplated disease is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.

[0413] For example, provided herein is a method for treating one or more diseases selected from the group consisting of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis in a patient in need thereof, the method comprising administering to the patient an effective amount of any compound disclosed herein or a disclosed pharmaceutical composition.

[0414] Combination therapy

[0415] In certain instances, a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with a second therapeutic agent.

[0416] In some embodiments, by administering a compound described herein with a second therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit, the benefit experienced by the patient can be increased.

[0417] In a specific embodiment, a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0418] In any event, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply the additive benefit of the two therapeutic agents, or the patient experiences a synergistic benefit.

[0419] In certain embodiments, when the compounds disclosed herein are administered in combination with a second therapeutic agent, different therapeutically effective doses of the compounds disclosed herein will be used to formulate pharmaceutical compositions and / or treatment regimens. The therapeutically effective doses of the drugs and other agents used in the combined treatment regimen are optionally determined by similar methods as described above for the active substance itself. In addition, the prevention / treatment methods described herein include the use of a metronome, i.e., providing more frequent, lower doses to minimize toxic side effects. In some embodiments, the combined treatment regimen includes the following treatment regimen: the compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered before, during, or after the start of the second drug treatment, and continues to any stage of the second drug treatment or after the termination of its treatment. It also includes a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a second drug used in combination, administered simultaneously or at different times and / or at reduced or increased intervals during treatment. Combined treatment also includes regular treatments that start and stop at different times to assist in the clinical management of patients.

[0420] It should be understood that the administration regimen for treating, preventing or improving the condition being sought to be alleviated is modified according to a variety of factors (e.g., the disease, disorder or condition suffered by the subject; the age, weight, sex, diet and medical condition of the subject). Therefore, in some cases, the actual dosage regimen used will be different, and in some embodiments, will deviate from the dosage regimen described herein.

[0421] For the combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, the specific drug employed, 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.

[0422] In combination therapy, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents are provided, by way of example only, in a single, unified form or in multiple forms (e.g., as a single pill or as two separate pills).

[0423] The compounds described herein, or their pharmaceutically acceptable salts, solvates or stereoisomers, and combination therapies, are administered before, during or after the occurrence of a disease or condition, and the time for administering a composition containing the compound is different. Therefore, in one embodiment, the compounds described herein are used as prophylactics and are continuously administered to subjects with a tendency to develop a condition or disease in order to prevent the occurrence of a disease or condition. In another embodiment, during or after the onset of symptoms, the compounds and compositions are administered to the subject as soon as possible. In a specific embodiment, after a disease or condition is detected or suspected, the compounds described herein are administered as soon as possible, and the administration time is the length of time necessary to treat the disease. In some embodiments, the length required for treatment is different, and the length of treatment is adjusted to suit the specific needs of each subject. For example, in a specific embodiment, the compounds described herein or formulations containing the compounds are administered for at least 2 weeks, about 1 month to about 5 years.

[0424] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are administered in combination with an adjuvant. In one embodiment, the therapeutic effect of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., the adjuvant itself has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Example

[0425] Based on the teachings contained herein and synthetic procedures known in the art, the compounds described herein can be prepared in a variety of ways. In the description of the following synthetic methods, it should be understood that, unless otherwise stated, all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental time and processing procedures, can be selected as standard conditions for the reaction. It should be understood by those skilled in the art of organic synthesis that the functionality present on each part of the molecule should be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions are obvious to those skilled in the art, so alternative methods are pointed out. The starting materials of the embodiments can be commercially available, or can be easily prepared by known materials by standard methods. At least some of the compounds identified as "intermediates" herein are considered to be compounds of the present disclosure.

[0426] 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]pyridazine-6(1,2)-cyclopentacyclooctan-8-one (Compound 1)

[0427]

[0428] To a stirred solution of (7-bromo-3-methyl-1,2,3-benzotriazol-5-yl)methyl methanesulfonate (1.6 g, 5.0 mmol, 1 eq.) and tert-butyl N-[(1R,2R)-2-hydroxycyclopentyl]carbamate (2 g, 10 mmol, 2 eq.) in THF at 0°C under nitrogen atmosphere, TBAI (184 mg, 0.50 mmol, 0.1 eq.) and NaH (0.14 g, 6 mmol, 1.2 eq.) were added in portions. The resulting mixture was stirred for 3 hours at 0°C under nitrogen atmosphere. The desired product was detected by LCMS. The reaction was quenched with water at room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous MeCN, gradient from 60% to 70% in 10 minutes; detector, UV 254 nm. Tert-butyl N-[(1R,2R)-2-[(7-bromo-3-methyl-1,2,3-benzotriazol-5-yl)methoxy]cyclopentyl]carbamate (1.2 g, 55%) was obtained as a white solid.

[0429] 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) at room temperature under nitrogen atmosphere, Pd2(dba)3 (250 mg, 0.27 mmol, 0.1 eq), Xantphos (4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (315 mg, 0.55 mmol, 0.2 eq) and Cs2CO3 (1770 mg, 5.5 mmol, 2 eq) were added portionwise. The resulting mixture was stirred at 100°C under nitrogen atmosphere overnight. The mixture was allowed to cool to room temperature. The desired product can be detected by LCMS. The residue was purified by reverse phase flash chromatography under the following conditions: chromatographic column, C18 silica gel; mobile phase, MeCN aqueous solution, gradient from 50% to 75% in 20 minutes; detector, UV 254 nm. Green solid N-[6-(([(1R,2R)-2-[(tert-butyloxycarbonyl)amino]cyclopentyl]oxymethyl)-1-methyl-1,2,3-benzotriazol-4-yl]carbamic acid tert-butyl ester (1 g, 85%) was obtained.

[0430] 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 eq) and 4M HCl in 1,4-dioxane (15 mL) was stirred at room temperature under nitrogen atmosphere for 3 hours. The target product can 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.

[0431] 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 eq) and 8-[(tert-butoxycarbonyl)(methyl)amino]-6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid (375 mg, 1.2 mmol, 1.2 eq) in DCM (5 mL) at room temperature under nitrogen atmosphere, DIEA (989 mg, 7.7 mmol, 8 eq) and HATU (545 mg, 1.4 mmol, 1.5 eq) were added portionwise. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The desired product was detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography under the following conditions: chromatographic column, C18 silica gel; mobile phase, aqueous MeCN (0.1% FA), gradient from 30% to 70% in 20 minutes; detector, UV254nm. Yellow solid 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-methylcarbamic acid tert-butyl ester (425 mg, 78%) was obtained.

[0432] 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 eq) and Pd2(dba)3 (62 mg, 0.07 mmol, 0.1 eq) in dioxane (8 mL) at room temperature under nitrogen atmosphere, Xantphos (78 mg, 0.14 mmol, 0.2 eq) and Na2CO3 (143 mg, 1.3 mmol, 2 eq) were added portionwise. The resulting mixture was stirred at 100°C under nitrogen atmosphere overnight. The precipitate was purified by LCM S was used to detect the target product. The mixture was cooled to room temperature. The residue was purified by reverse phase flash chromatography under the following conditions: chromatographic column, C18 silica gel; mobile phase, MeCN aqueous solution, gradient from 60% to 70% in 10 minutes; detector, UV254nm. Yellow solid 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]octacos-1(26),3,5,8,10(28),20,22,24-octen-24-yl]carbamic acid tert-butyl ester (310 mg, 86%) was obtained.

[0433] At room temperature and under nitrogen atmosphere, 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]octacos-1(26),3,5,8,10(28),20,22,24-octen-24-yl]carbamate (280 mg, 0.53 mmol, 1 equivalent) and 4M A solution of HCl in 1,4-dioxane (10 mL) was stirred for 3 hours. The target product can be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography under the following conditions: chromatographic column, C18 silica gel; mobile phase, MeCN aqueous solution, gradient from 30% to 70% in 20 minutes; detector, UV254nm. A white solid (13R,17R)-7-methyl-24-(methyl)- amino)-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-octen-19-one (71 mg, 31%). LCMS: [M+H]+=434.10. NMR: 1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.20(d,J=4.5Hz,1H),8.14(s,1H),7.85(s,1H),7.57(d, J=5.1Hz,1H),7.30(s,1H),6.40(s,1H),4.94(d,J=14.4Hz,1H),4.60(d,J=14.5Hz,1H),4.28( s,3H),3.88–3.80(m,1H),3.72(q,J=8.5Hz,1H),2.91(d,J=4.8Hz,3H),2.28(q,J=8.8,8.0Hz, 1H), 2.09 (d, J=12.2Hz, 1H), 1.73 (s, 1H), 1.52 (dq, J=19.4, 9.7, 8.7Hz, 2H), 1.25–1.10 (m, 1H).

[0434] Example 2: (1 3 E,1 4 E,6 1 R,6 2 R)-3 1 -methyl-1 7 -(Methylamino)-3 1Synthesis of H-5-oxa-2,7-diaza-1(5,3),3(4,6)-dipyrazolo[1,5-a]pyrimidine-6(1,2)-cyclopentacyclooctan-8-one (Compound 2)

[0435]

[0436] 7-((tert-Butyloxycarbonyl)(methyl)amino)-5-((6-((((1R,2R)-2-((tert-Butyloxycarbonyl)amino)cyclopentyl)oxy)methyl)-1-methyl-1H-benzo[d][1,2,3]triazol-4-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (2c)

[0437] To a solution of 2a (100 mg, 0.235 mmol, 1.00 equiv) in anhydrous dioxane (4.7 mL) were added 2b (86 mg, 0.25 mmol, 1.1 equiv), CsCO (153 mg, 0.470 mmol, 2.00 equiv), Pd(dba) (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 N 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) to provide a white solid 2c (132 mg, 83%). LCMS [M+H] + =680.21. 1 HNMR (300MHz, CDCl3) δ8.94 (s, 1H), 8.39 (s, 1H), 8.36 (s, 1H), 7.33 (s, 1H), 6.51 (s, 1H), 5.02-4.89 (m, 1H), 4.87 (s, 2H), 4.48 (q, J=7.1Hz, 2H) , 4.31(s, 3H), 4.01(s, 2H), 3.38(s, 3H), 2.28-2.11(m, 1H), 2.03-1.94( m, 1H), 1.82-1.64 (m, 4H), 1.51-1.43 (m, 3H), 1.40 (s, 9H), 1.39 (s, 9H).

[0438] 7-((tert-Butyloxycarbonyl)(methyl)amino)-5-((6-((((1R,2R)-2-((tert-Butyloxycarbonyl)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)

[0439] 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 hours. The solvent was removed under reduced pressure. Purification by silica gel flash column chromatography (0-80% MeOH in DCM) gave 2d (71 mg, 57%) as a white solid. LCMS [M+H] + =652.18.

[0440] 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)

[0441] To a solution of 2d (71 mg, 0.11 mmol, 1.0 equiv) in a mixture of DCM / THF (1:1, 2.0 mL) at 0°C was added TFA (0.85 mL, 11 mmol, 100 equiv). The resulting mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure to give 2e (60 mg, quantitative) as a brown oil. [M+H] + =452.18.

[0442] (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]pyrimidin-6(1,2)-cyclopentacyclooctan-8-one

[0443] To a solution of 3e (50 mg, 0.11 mmol, 1.0 equiv) in a mixed solvent of DCE (2.2 mL) and DMF (0.22 mL), HATU (42 mg, 0.11 mmol, 1.0 equiv) and DIEA (0.15 mL, 0.88 mmol, 8.0 equiv) were added. The reaction mixture was stirred at room temperature for 2 hours. The solution was quenched by adding water (2.0 mL), extracted with DCM (3x5 mL), dried over Na2SO4 and concentrated under reduced pressure. The product was purified by flash column chromatography on silica gel (R f =0.45, DCM / MeOH, 95:5) provided the title compound as a white solid (20 mg, 42%). Formula: C 21 H 23N9O2.MW:433.48.LCMS:[M+H] + =434.12. 1 HNMR (300MHz, CDCl3) δ8.78 (d, J = 3.5Hz, 1H), 8.64 (s, 1H), 8.34 (s, 1H), 8.09 (s, 1H), 6. 97(s,1H),6.33(q,J=5.0Hz,1H),5.53(s,1H),5.06(d,J=14.7Hz,1H),4.68–4.54(m,1H ),4.29(s,3H),4.03–3.93(m,1H),3.84(q,J=8.4Hz,1H),3.12(d,J=5.2Hz,3H),2.71–2 .56(m,1H),2.17–2.07(m,1H),1.93–1.76(m,1H),1.72–1.51(m,2H),1.35–1.18(m,2H).

[0444] Following synthetic experimental procedures similar to those described in Examples 1 and 2, the following compounds were prepared.

[0445] (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]pyridazine-6(1,2)-cyclopentacyclooctan-8-one (Compound 3)

[0446]

[0447] White solid. f =0.40 (DCM / MeOH, 95:5). Formula: C 21 H 23 N9O2.MW:433.48.LCMS[M+H] + =434.20. 1H NMR (300MHz, CDCl3) δ8.97 (d, J = 3.9Hz, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.63 (s, 1H), 7.44 (s,1H),6.24(q,J=5.2Hz,1H),5.75(s,1H),4.97(d,J=13.3Hz,1H),4.63(s,3H),4.47(d ,J=13.4Hz,1H),3.95–3.76(m,1H),3.46(q,J=8.6Hz,1H),2.99(d,J=5.1Hz,3H),2.46–2 .29(m,1H),2.10–1.98(m,1H),1.70–1.61(m,1H),1.57–1.38(m,2H),1.20–1.07(m,1H).

[0448] (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]pyridazine-6(1,2)-cyclopentacyclooctan-8-one (Compound 4)

[0449]

[0450] White solid. f =0.40 (DCM / MeOH, 95:5). Formula: C 21 H 23 N9O2.MW:433.48.LCMS:[M+H] + =434.33. 1H NMR (300MHz, CDCl3) δ9.24 (d, J = 4.3Hz, 1H), 8.24 (s, 1H), 8.08 (s, 1H), 7.30 (s, 1H), 7.13 (s, 1H) ,6.07(s,1H),5.70(s,1H),5.00(d,J=14.2Hz,1H),4.59(d,J=14.3Hz,1H),4.51(s,3H),4.19-3 .99(m,1H),3.80(q,J=8.4Hz,1H),3.07(d,J=5.2Hz,3H),2.56(dd,J=11.5,6.5Hz,1H),2.11(dd ,J=7.6,3.6Hz,1H),1.84(q,J=10.0,7.7Hz,1H),1.61(q,J=10.0,8.9Hz,2H),1.34-1.15(m,2H).

[0451] (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]pyridazine-6(1,2)-cyclopentacyclooctan-8-one (Compound 5)

[0452]

[0453] White solid. f =0.40 (DCM / MeOH, 95:5). Formula: C 21 H 23 N9O2.MW:433.48.LCMS:[M+H] + =434.18. 1 H NMR (300MHz, CDCl3) δ8.65 (d, J = 6.9Hz, 1H), 8.60 (s, 1H), 8.13 (s, 1H), 7.73 (s, 1H),6.95(s,1H),6.02(d,J=5.1Hz,1H),5.75(s,1H),4.89(d,J=12.5Hz,1H),4 .50(d,J=12.5Hz,1H),4.36–4.30(m,1H),4.28(s,3H),4.08(t,J=3.2Hz,1H),3 .05(d,J=5.1Hz,3H),2.52–2.31(m,1H),2.05–1.86(m,2H),1.83–1.65(m,3H).

[0454] (61 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]pyridazine-6(1,2)-cyclopentacyclooctan-8-one (Compound 6)

[0455]

[0456] White solid. f =0.40 (DCM / MeOH, 95:5). Formula: C 21 H 23 N9O2.MW:433.48.LCMS:[M+H] + =434.20. 1 H NMR (300MHz, Methanol-d4) δ8.77(d,J=3.9Hz,1H),8.26(s,1H),7.87(s,1H),7.65(s,1H),6.01(s,1H),4.85(d,J=12.9Hz,1H) ,4.57(s,3H),4.49(d,J=12.9Hz,1H),3.86–3.70(m,2H),3.07(s,3H),2.51–2.37(m,1H),2.08–1.86(m,2H),1.81–1.56(m,3H).

[0457] (1 5 E,3 4 E,6 1 S,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]pyridazine-6(1,2)-cyclopentacyclooctan-8-one (Compound 7)

[0458]

[0459] White solid. f =0.35 (DCM / MeOH, 95:5). Formula: C 21 H 23 N9O2.MW:433.48.LCMS:[M+H] + =434.20. 1H NMR (300MHz, CDCl3) δ8.66 (d, J = 6.8Hz, 1H), 8.52 (s, 1H), 8.13 (s, 1H), 7.30 (s, 1H) ),7.10(s,1H),5.91(d,J=5.7Hz,1H),5.69(s,1H),4.87(d,J=12.1Hz,1H),4.50( s,2H),4.46(d,J=11.7Hz,2H),4.30(dt,J=7.3,4.0Hz,1H),4.17–4.03(m,1H),3. 06(d,J=5.2Hz,3H),2.40(d,J=10.4Hz,1H),2.12–1.90(m,2H),1.87–1.72(m,3H).

[0460] (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]pyrimidine-6(1,2)-cyclopentacyclooctan-8-one (Compound 10)

[0461]

[0462] White solid. f =0.30 (DCM / MeOH, 95:5). Formula: C 19 H 23 N9O2.MW:433.48.LCMS:[M+H] + =434.12. 1 H NMR(300MHz, CDCl3)δ8.76(s,1H),8.53(s,1H),8.33(s,1H),7.40(s,1H),7.34(s,1H),6 .26(d,J=5.8Hz,1H),5.47(s,1H),5.01(d,J=14.2Hz,1H),4.59(d,J=14.3Hz,1H),4.51(s ,3H),3.95(t,J=8.5Hz,1H),3.81(q,J=8.4Hz,1H),3.11(d,J=5.2Hz,3H),2.72–2.53(m, 1H), 2.11 (dd, J=11.5, 7.0Hz, 1H), 1.83 (d, J=8.9Hz, 1H), 1.65 (s, 1H), 1.32–1.20 (m, 2H).

[0463] (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]pyrimidine-6(1,2)-cyclopentacyclooctan-8-one (Compound 11)

[0464]

[0465] White solid. f =0.40 (DCM / MeOH, 95:5). Formula: C 21 H 23 N9O2.MW:433.48.LCMS:[M+H] + =433.99. 1 H NMR (300MHz, CDCl3) δ9.23 (s, 1H), 8.38 (s, 1H), 8.32 (d, J = 7.4Hz, 1H), 8.21 ( s,1H),6.98(s,1H),6.28(d,J=5.4Hz,1H),5.59(s,1H),4.87(d,J=11.7Hz,1 H),4.50(d,J=11.9Hz,1H),4.39–4.30(m,1H),4.28(s,3H),4.16(s,1H),3.1 0(d,J=5.2Hz,3H),2.37–2.26(m,1H),2.04–1.90(m,2H),1.85–1.56(m,3H).

[0466] (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]pyridine-3(4,6)-benzo[d]imidazo-6(1,2)-cyclopentacyclooctan-8-one (Compound 12)

[0467]

[0468] White solid. f =0.35 (DCM / MeOH, 95:5). Formula: C 22 H 24N8O2.MW:432.49.LCMS:[M+H] + =433.15. 1 H NMR (300MHz, CDCl3) δ9.35 (d, J = 4.2Hz, 1H), 8.26 (s, 1H), 8.05 (s, 1H), 7.81 (s, 1H), 7. 62(s,1H),6.89(s,1H),6.02(s,1H),5.74(s,1H),5.07(d,J=14.1Hz,1H),4.58(d,J=1 4.1Hz,1H),4.06(dt,J=10.0,5.2Hz,1H),3.87(s,4H),3.03(d,J=5.0Hz,3H),2.58(dd ,J=12.0,6.8Hz,1H),2.16–2.02(m,1H),1.96–1.78(m,2H),1.63(p,J=9.3,8.6Hz,2H).

[0469] (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]pyridazine-3(4,6)-benzo[d]imidazo-6(1,2)-cyclopentacyclooctan-8-one (Compound 13)

[0470]

[0471] White solid. f =0.35 (DCM / MeOH, 95:5). Formula: C 22 H 24 N8O2.MW:432.49.LCMS:[M+H] + =433.08. 1H NMR (300MHz, CDCl3): δ8.78(d,J=6.3Hz,1H),8.49(s,1H),8.09(s,1H),7.80(s,1 H),7.56(s,1H),6.91(s,1H),5.88(d,J=5.4Hz,1H),5.72(s,1H),4.91(d,J=12.4H z,1H),4.49(d,J=12.4Hz,1H),4.21(s,1H),4.06(d,J=3.5Hz,1H),3.85(s,3H),3 .02(d,J=5.1Hz,3H),2.54–2.37(m,1H),1.97(d,J=9.3Hz,2H),1.84–1.60(m,3H).

[0472] Example 3: Synthesis of additional synthetic intermediates

[0473] Synthetic intermediates for certain disclosed compounds were prepared according to the following Schemes ag.

[0474] Plan A:

[0475]

[0476] Option B:

[0477]

[0478] Option c:

[0479]

[0480] Option d:

[0481]

[0482] Plan e:

[0483]

[0484] Plan f:

[0485]

[0486] Example 5: TYK2 JH2 domain binding assay

[0487] By the following The binding constants of the compounds described herein for the JH2 domain were determined using the DiscoveRX protocol. A partial length construct of human TYK2 (JH2 domain-pseudokinase) (based on amino acids G556 to D888 of the reference sequence NP_003322.3) and a fusion protein of the DNA binding domain of NFkB were expressed in transiently transfected HEK293 cells. Extracts were prepared from these HEK293 cells in M-PER extraction buffer (Pierce) in the presence of a protease inhibitor cocktail (Roche) and a phosphatase inhibitor cocktail set II (Merck) according to the manufacturer's instructions. The TYK2 (JH2 domain-pseudokinase) fusion protein was labeled with a chimeric double-stranded DNA tag containing a NFkB binding site fused to an amplicon for qPCR readings, which was added directly to the expression extract (the final concentration of the DNA tag in the binding reaction was 0.1 nM).

[0488] Streptavidin-coated magnetic beads (Dynal M280) were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for binding assays. Ligand beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and reduce nonspecific binding.

[0489] Binding reactions were assembled by combining 16 μl DNA-labeled kinase extract, 3.8 μl ligand affinity beads and 0.18 μl test compound (PBS / 0.05% Tween 20 / 10 mM DTT / 0.1% BSA / 2 μg / ml sonicated salmon sperm DNA). The extracts were used directly in the binding assay without any enzyme purification steps, and the total stock dilution was ≥10,000 times (final DNA-labeled enzyme concentration <0.1 nM). The extracts were loaded with DNA tags and diluted into the binding reactions in a two-step process. The first extract was diluted 1:100 in 1× binding buffer (PBS / 0.05% Tween 20 / 10 mM DTT / 0.1% BSA / 2 μg / ml sonicated salmon sperm DNA) containing 10 nM DNA tag. The dilution was allowed to equilibrate at room temperature for 15 minutes and then 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 and three DMSO control points. All compounds used for Kd measurements were dispersed in 100% DMSO by acoustic transmission (contactless dispersion). Compounds were then diluted directly into the assay samples so that the final concentration of DMSO was 0.9%. All reactions were performed in 384-well polypropylene plates. The final volume of each sample was 0.02 mL. The assay samples were incubated at room temperature with shaking for 1 hour. The beads were then pelleted and washed with wash buffer (1× PBS, 0.05% Tween 20) to remove displaced kinases and test compounds. The washed matrix was resuspended in elution buffer (1× PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluate was measured by qPCR. Assemble the qPCR reaction by adding 2.5 μL of kinase eluate to 7.5 μL of qPCR master mix containing 0.15 μM amplicon primers and 0.15 μM amplicon probe. The qPCR protocol consisted of a hot start at 95 °C for 10 min, followed by 35 cycles of 95 °C for 15 sec and 60 °C for 1 min.

[0490] Test compounds were prepared as 111× stock solutions in 100% DMSO. Kds were determined using an 11-point 3-fold compound dilution series and three DMSO control points. All compounds used for Kd measurements were dispersed in 100% DMSO by acoustic transmission (non-contact dispersion). Compounds were then diluted directly into the assay samples to a final DMSO concentration of 0.9%. Kds were determined using the highest compound concentration of 30,000 nM. Kd measurements were performed in duplicate.

[0491] The binding constant (Kds) was calculated from the standard dose response curve using the Hill equation:

[0492]

[0493] The Hill slope was set to -1. Nonlinear least squares fitting and the Levenberg-Marquardt algorithm (Levenberg, K., A method for the solution of certain non-linear problems in least squares, Q. Appl. Math. 2, 164-168 (1944)) were used for curve fitting.

[0494] The results are shown in Table 2.

[0495] Example 5: INFα induces pSTAT5 in human PBMCs

[0496] Fresh human PBMCs were resuspended in RPMI 1640 medium containing 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 10uM, 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 using the Phospho STAT5 (Tyr693) kit (Meso Scale Discovery) according to the manufacturer's protocol.

[0497] The inhibition rate was calculated as: relative pSTAT5 signal of each well = pSTAT5 signal of each well - baseline average pSTAT5 signal.

[0498] Inhibition percentage = (average pSTAT5 signal of INFα-treated wells - relative value of pSTAT5 signal in each well containing compound) / average pSTAT5 signal of INFα-treated wells * 100%

[0499] Curves were plotted as percent inhibition (y-axis) versus compound concentration (x-axis) and fitted as log(inhibitor) versus normalized response - variable slope using GraphPad Prism 7.0 software.

[0500] The results are shown in Table 3.

[0501] Table 2.

[0502]

[0503]

[0504] A≥30000nM; B≥10000nM and <30000nM; C≥1000nM and <10000nM; D≥10nM and <1000nM; E<10nM.

[0505] Table 3.

[0506]

[0507] A≥100nM; B<100nM.

[0508] Incorporated by Reference

[0509] All publications and patents mentioned herein, including those listed below, are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication or patent was specifically and individually incorporated by reference. In the event of a conflict, the present application, including any definitions herein, will control.

[0510] Equivalents and scope

[0511] In the claims, articles such as "a, an," and "the" may refer to one or more unless otherwise stated or obvious from the context. A claim or description containing "or" between one or more members of a group is considered satisfied if one, more, or all of the members of the group are present in, used in, or otherwise associated with a given product or process, unless otherwise stated or obvious from the context. The present application includes embodiments in which exactly one member of the group is present in, used in, or otherwise associated with a given product or process. The present application includes embodiments in which more than one or all of the group members are present in, used in, or otherwise associated with a given product or process.

[0512] In addition, the present application covers all variations, combinations and arrangements, in which one or more limitations, elements, clauses and descriptive terms in one or more of the listed claims are introduced into another claim. For example, any claim that is subordinate to another claim can be modified to include one or more limitations found in any other claim that is subordinate to the same basic claim. When elements are presented in a list form (for example, in the format of Markush groups), each subgroup of elements is also disclosed, and any element can be deleted from the group. It should be understood that, in general, when the present application or aspects of the present application are referred to as including specific elements and / or features, certain embodiments of the present application or aspects of the present application are composed of or substantially composed of these elements and / or features. For simplicity, these embodiments are not specifically described in the same words here. It should also be noted that the terms "comprising" and "containing" are intended to remain open and allow the inclusion of additional elements or steps. Endpoints are also included when a range is given. In addition, unless otherwise stated or apparent from the context and the understanding of one of ordinary skill in the art, numerical values ​​expressed in ranges may have any specific value or sub-range within the stated range in different embodiments of the present application, accurate to one-tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0513] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If any cited reference conflicts with this specification, the specification shall prevail. In addition, any specific embodiment of the present application that belongs to the prior art may be explicitly excluded from any one or more claims. Since such embodiments are considered to be known to those skilled in the art, they may be excluded even if the exclusion is not explicitly stated herein. Any specific embodiment of the present application may be excluded from any claim for any reason, whether or not it is related to the existence of the prior art.

[0514] Those skilled in the art will recognize, or be able to determine using only routine experiments, many equivalents of the specific embodiments described herein. The scope of the present embodiment described herein is not limited to the above description, but is limited by the appended claims. Those of ordinary skill in the art will recognize that various changes and modifications may be made to this description without departing from the spirit or scope of the present application as defined by the claims of the application.

Claims

1. A compound represented by formula I: or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: Ring A is a 6,5- or 6,6-fused bicyclic heteroaryl containing two, three or four ring nitrogens; R A Each occurrence is independently selected from: hydrogen, halogen, -NR a R b , C1-C6 alkyl and C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy may be optionally substituted by one or more halogens or deuterium; Ring B is a 6,5- or 6,6-fused bicyclic heteroaryl containing one, two or three ring nitrogens; R B Each occurrence is independently selected from: hydrogen, halogen, -NR a R b , C1-C6 alkyl and C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy may be optionally substituted by one or more halogens or deuterium; Y is selected from: O, N(R a )、S(O) w , CH2 and bond; Z is selected from: N(R a ) and O; R 1 Each occurrence is independently selected from: deuterium, halogen, hydroxyl, -NR a R b , cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl and C1-C6 alkoxy; wherein R 4 May be substituted on available carbons with hydroxyl groups or one or more halogens; R 2 and R 3 are each independently selected from: hydrogen, deuterium and C1-C6 alkyl optionally substituted by one or more halogens; or R 2 and R 3 Can be linked together with the carbon to which they are attached to form a C3-C6 cycloalkyl group; R a and R b Each occurrence is independently selected from: hydrogen and C1-C6 alkyl, wherein C1-C6 alkyl may be optionally 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.

2. The compound according to claim 1, wherein ring A is represented by: in Q is N and T is C; or Q is C and T is N; and R A Selected from: -N(H)CH3, -NH2, hydrogen and -OCH3; wherein * represents the point of attachment to the -NH- group in formula I.

3. The compound according to claim 1 or 2, wherein ring A is selected from:

4. The compound according to claim 1, wherein ring A is represented by: Wherein T is N or CH; R A1 is selected from: -N(H)CH3, -NH2, hydrogen, and -OCH3; and R A2 Selected from: hydrogen and -CH3; wherein * represents the point of attachment to the -NH- group in formula I.

5. The compound according to claim 1 or 4, wherein ring A is selected from:

6. The compound according to any one of claims 1 to 5, wherein ring B is represented by: in V is N(R V ), W is N, and X is N; or V is N, W is N (R V ), and X is N; or V is N, W is N, and X is N (R X );or V is N, W is C (R W ), and X is N(R X );or V is N(R V ), W is C(R W ), and X is N; or V is N(R V ), W is N, and X is C(R X );or V is N, W is N (R W ), and C is C(R X );or V is C(R V ), W is N(R W ), and X is N; or V is C(R V ), W is N, and X is N(R X );or V is N, W is C (R W ), and X is C(R X );or V is C(R V ), W is C(R W ), and 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, W is C (R W ), and X is N; or V is N, W is C (R W ), and X is O; and R V , R W and R X Each is independently selected from: hydrogen and C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted by one or more substituents, and the substituents are each independently selected from: deuterium, halogen and hydroxyl; wherein * represents the point of attachment to the -NH- group in formula I.

7. The compound according to any one of claims 1 to 6, wherein Ring B is represented by: Where R V , R W and R X Each is independently selected from: hydrogen, -CH3 and -CD3.

8. The compound according to any one of claims 1 to 6, wherein Ring B is represented by: Where R V , R W and R X Each is independently selected from: hydrogen, -CH3 and -CD3.

9. The compound according to any one of claims 1 to 5, wherein Ring B is represented by: in U, V, W, X, Y and Z are each independently selected from: N and C (R B ); wherein one or two of U, V, W, X, Y and Z are N; and R B Each occurrence is independently selected from: hydrogen, halogen, C1-C3 alkyl, and C1-C3 alkoxy; wherein * represents the point of attachment to the -NH- group in formula I.

10. The compound according to any one of claims 1-5 and 9, wherein ring B is selected from: Where R B Selected from: hydrogen, -CH3 and -OCH3.

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

12. A compound according to any one of claims 1, 2 and 6, wherein the compound is represented by Formula II:

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

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

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

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

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

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

19. A compound according to any one of claims 12 to 18, wherein R X , R W and R V Each is hydrogen or C1-C6 alkyl optionally substituted by one or more deuterium.

20. A compound according to any one of claims 12 to 19, wherein R X , R W and R V Each is independently selected from: hydrogen, -CH3 and -CD3.

21. The compound of any one of claims 1-20, wherein Y is selected from the group consisting of: O, NH, NCH3, S, S(O) and S(O)2.

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

23. The compound according to any one of claims 1-22, wherein Z is selected from: O, NH and NCH3.

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

25. A compound according to any one of claims 1 to 24, wherein R 2 and R 3 Each independently selected from: hydrogen, deuterium, -CH3 and -CF3; or R 2 and R 3 Together with the carbon to which they are attached they form a cyclopropyl group.

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

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

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

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

30. A compound according to any one of claims 1 to 29, wherein p is 1, and R 4 It is hydroxyl or -CH2OH.

31. A compound represented by formula III: or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: Q is N and T is C; or Q is C, and T is N; wherein Q and T are each a member of a heteroaromatic ring system; V is N(R V ), W is N, and X is N; or V is N, W is N (R V ), and X is N; or V is N, W is N, and X is N (R X );or V is N, W is C (R W ), and X is N(R X );or V is N(R V ), W is C(R W ), and X is N; or V is N(R V ), W is N, and X is C(R X );or V is N, W is N (R W ), and C is C(R X );or V is C(R V ), W is N(R W ), and X is N; or V is C(R V ), W is N, and X is N(R X );or V is N, W is C (R W ), and X is C(R X );or V is C(R V ), W is C(R W ), and 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; wherein V, W and X are each a member of a heteroaromatic ring system; Y is selected from: O, N(R a )、S(O) w , CH2 and bond; R V , R W and R X Each is independently selected from: hydrogen and C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted with one or more substituents, each of which is independently selected from: deuterium, halogen and hydroxyl; R 1 is hydrogen or C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted by one or more halogens or deuterium; R 2 and R 3 are each independently selected from: hydrogen, deuterium and C1-C6 alkyl optionally substituted by one or more halogens; or R 2 and R 3 Can be linked together with the carbon to which they are attached to form a C3-C6 cycloalkyl group; R 4 Each occurrence is independently selected from: deuterium, halogen, hydroxyl, -NR a R b , cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl and C1-C6 alkoxy; wherein R 4 May be substituted on available carbons with hydroxyl groups or one or more halogens; R 5 and R 6 are each independently selected from: hydrogen, deuterium and C1-C6 alkyl optionally substituted by one or more halogens; or R 5 and R 6 Can be linked together with the carbon to which they are attached to form a C3-C6 cycloalkyl group; R a and R b Each occurrence is independently selected from: hydrogen and C1-C6 alkyl, wherein C1-C6 alkyl may be optionally substituted with one or more 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.

32. The compound according to claim 31, wherein the compound is represented by:

33. The compound according to claim 31, wherein the compound is represented by:

34. The compound according to claim 31, wherein the compound is represented by:

35. The compound according to claim 31, wherein the compound is represented by:

36. The compound according to claim 31, wherein the compound is represented by:

37. The compound according to claim 31, wherein the compound is represented by:

38. A compound according to any one of claims 31-37, wherein R X , R W and R V Each is a C1-C6 alkyl group optionally substituted by one or more deuterium groups.

39. A compound according to any one of claims 31-38, wherein R X , R W and R V Each is independently selected from: -CH3 and -CD3.

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

41. A compound according to any one of claims 31-40, wherein R 1 is C1-C6 alkyl optionally substituted by one or more deuterium.

42. A compound according to any one of claims 31-41, wherein R 1 Selected from: -CH3 and -CD3.

43. A compound according to any one of claims 31-42, wherein R 2 and R 3 Each independently selected from: hydrogen, deuterium, -CH3 and -CF3; or R 2 and R 3 Together with the carbon to which they are attached they form a cyclopropyl group.

44. according to the compound described in any one of claims 31-43, wherein R 5 and R 6 Each is independently selected from: hydrogen, deuterium, -CH3 and -CF3.

45. A compound according to any one of claims 31-44, wherein m is 1.

46. ​​A compound according to any one of claims 31-44, wherein m is 2.

47. A compound according to any one of claims 31-46, wherein n is 0.

48. A compound according to any one of claims 31-46, wherein n is 1.

49. according to the compound described in any one of claims 31-48, wherein p is 1, and R 4 It is hydroxyl or -CH2OH.

50. The compound represented by formula IV: or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: Q is N and T is C; or Q is C and T is N; wherein Q and T are each a member of a heteroaromatic ring system; V is N(R V ), W is N, and X is N; or V is N, W is N (R V ), and X is N; or V is N, W is N, and X is N (R X );or V is N, W is C (R W ), and X is N(R X );or V is N(R V ), W is C(R W ), and X is N; or V is N(R V ), W is N, and X is C(R X );or V is N, W is N (R W ), and C is C(R X );or V is C(R V ), W is N(R W ), and X is N; or V is C(R V ), W is N, and X is N(R X );or V is N, W is C (R W ), and X is C(R X );or V is C(R V ), W is C(R W ), and 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; wherein V, W and X are each a member of a heteroaromatic ring system; Y is selected from: O, N(R a )、S(O) w , CH2 and bond; R V , R W and R X Each is independently selected from: hydrogen and C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted with one or more substituents, each of which is independently selected from: deuterium, halogen and hydroxyl; R 1 is hydrogen or C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted with one or more deuterium; R 2 and R 3 are each independently selected from: hydrogen, deuterium and C1-C6 alkyl which may be optionally substituted with one or more halogens; or R 2 and R 3 Together with the carbon to which they are attached, they may form a C3-C6 cycloalkyl group; R 4 Each occurrence is independently selected from: deuterium, halogen, hydroxyl, -NR a R b , cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl and C1-C6 alkoxy; wherein R 4 May be substituted on available carbons with hydroxyl groups or one or more halogens; R a and R b Each occurrence is independently selected from: hydrogen and C1-C6 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.

51. The compound according to claim 50, wherein the compound is represented by:

52. The compound according to claim 50, wherein the compound is represented by:

53. The compound according to claim 50, wherein the compound is represented by:

54. The compound according to claim 50, wherein the compound is represented by:

55. The compound according to claim 50, wherein the compound is represented by:

56. The compound according to claim 50, wherein the compound is represented by:

57. A compound according to any one of claims 50-56, wherein R X , R W and R V Each is a C1-C6 alkyl group optionally substituted by one or more deuterium groups.

58. A compound according to any one of claims 50-57, wherein R X , R W and R V Each is independently selected from: -CH3 and -CD3.

59. A compound according to any one of claims 50-58, wherein Y is O.

60. A compound according to any one of claims 50-59, wherein R 1 is C1-C6 alkyl optionally substituted by one or more deuterium.

61. according to the compound described in any one of claims 50-60, wherein R 1 Selected from: -CH3 and -CD3.

62. A compound according to any one of claims 50-61, wherein R 2 and R 3 Each independently selected from: hydrogen, deuterium, -CH3 and -CF3; or R 2 and R 3 Together with the carbon to which they are attached they form a cyclopropyl group.

63. A compound according to any one of claims 50-62, wherein m is 1.

64. A compound according to any one of claims 50-62, wherein m is 2.

65. according to the compound described in any one of claims 50-64, wherein p is 1, and R 4 It is hydroxyl or -CH2OH.

66. A compound represented by formula V: or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein: Q is N and T is C; or Q is C and T is N; wherein Q and T are each a member of a heteroaromatic ring system; V is N(R V ), W is N, and X is N; or V is N, W is N (R V ), and X is N; or V is N, W is N, and X is N (R X );or V is N, W is C (R W ), and X is N(R X );or V is N(R V ), W is C(R W ), and X is N; or V is N(R V ), W is N, and X is C(R X );or V is N, W is N (R W ), and C is C(R X );or V is C(R V ), W is N(R W ), and X is N; or V is C(R V ), W is N, and X is N(R X );or V is N, W is C (R W ), and X is C(R X );or V is C(R V ), W is C(R W ), and 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; wherein V, W and X are each a member of a heteroaromatic ring system; Z is selected from: N(R a ) and O; R V , R W and R X Each is independently selected from: hydrogen and C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted with one or more substituents, each of which is independently selected from: deuterium, halogen and hydroxyl; R 1 is hydrogen or C1-C6 alkyl; wherein the C1-C6 alkyl may be optionally substituted with one or more deuterium; R 2 and R 3 are each independently selected from: hydrogen, deuterium and C1-C6 alkyl which may be optionally substituted by one or more halogens; or R 2 and R 3 May be linked together with the carbon to which they are attached to form a C1-C6 cycloalkyl group; R 4 Each occurrence is independently selected from: deuterium, halogen, hydroxyl, -NR a R b , cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl and C1-C6 alkoxy; wherein R 4 May be substituted on available carbons with hydroxyl groups or one or more halogens; R a and R b is independently selected at each occurrence from: hydrogen and C1-C6 alkyl, wherein C1-C6 alkyl may be optionally substituted with one or more deuterium; m is 1 or 2; and p is 0, 1, 2, 3 or 4.

67. The compound according to claim 66, wherein the compound is represented by:

68. The compound according to claim 66, wherein the compound is represented by:

69. The compound according to claim 66, wherein the compound is represented by:

70. The compound according to claim 66, wherein the compound is represented by:

71. The compound of claim 66, wherein the compound is represented by:

72. The compound of claim 66, wherein the compound is represented by:

73. according to the compound described in any one of claims 66-72, wherein R X , R W and R V Each is a C1-C6 alkyl group optionally substituted by one or more deuterium groups.

74. according to the compound described in any one of claims 66-73, wherein R X , R W and R V Each is independently selected from: -CH3 and -CD3.

75. according to the compound described in any one of claims 66-74, wherein R 1 is C1-C6 alkyl optionally substituted by one or more deuterium.

76. according to the compound described in any one of claims 66-75, wherein R 1 Selected from: -CH3 and -CD3.

77. A compound according to any one of claims 66-76, wherein R 2 and R 3 Each independently selected from: hydrogen, deuterium, -CH3 and -CF3; or R 2 and R 3 Together with the carbon to which they are attached they form a cyclopropyl group.

78. A compound according to any one of claims 66-77, wherein m is 1.

79. A compound according to any one of claims 66-77, wherein m is 2.

80. A compound according to any one of claims 66-79, wherein p is 1, and R 4 It is hydroxyl or -CH2OH.

81. A compound selected from: or a pharmaceutically acceptable salt and / or stereoisomer thereof.

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

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

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

85. The method of claim 84, wherein inhibiting TYK2 activity is associated with treating a disease or condition 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 of treating a TYK2-mediated disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-81, or a pharmaceutical composition of claim 82.

87. The method of claim 86, wherein the TYK2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a transplantation-related disease.

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

89. A method of treating one or more diseases selected from the group consisting of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of any one of claims 1-81, or a pharmaceutical composition of claim 82.

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