Substituted heterocyclic compounds and their use in medicine

Abstract

The present application discloses a class of substituted heterocyclic compounds and their use in medicine, particularly as a drug for treating neurodegenerative diseases. Specifically, the present application relates to a compound represented by the general formula (I) or its stereoisomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or its prodrug, and their use as a drug, particularly as a TYK2 inhibitor and in the preparation of a drug for treating neurodegenerative diseases.

Description

Invention Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to a substituted heterocyclic compound and its use in the preparation of pharmaceuticals, particularly in the preparation of pharmaceuticals for treating neurodegenerative diseases. The invention also relates to pharmaceutical compositions comprising this type of derivative, and their use as TYK2 inhibitors and in the preparation of pharmaceuticals for treating neurodegenerative diseases. Background of the Invention

[0002] Janus kinases (JAKs) are intracellular non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. The JAK family plays a crucial role in cytokine-dependent proliferation regulation and cellular functions involved in immune responses. Cytokines bind to their receptors, causing receptor dimerization, which promotes both interphosphorylation of JAKs and phosphorylation of specific tyrosine motifs within the cytokine receptors. STATs that recognize these phosphorylated motifs accumulate on the receptors and are then activated during JAK-dependent tyrosine phosphorylation. Upon activation, STATs dissociate from their receptors, dimerize, and translocate to the nucleus, binding to specific DNA sites and altering transcription.

[0003] Currently, there are four known mammalian JAK family members: JAK1 (Janus kinase-1), JAK2 (Janus kinase-2), JAK3 (Janus kinase, leukocyte, JAKL, L-JAK, and Janus kinase-3), and TYK2 (protein tyrosine kinase 2). Different members of the Janus kinase family are responsible for transmitting signals of different cytokines and their receptors. JAK1, JAK2, and TYK2 are widely expressed, while JAK3 has been reported to be preferentially expressed in natural killer (NK) cells but not in other T cells.

[0004] TYK2 is involved in the signal transduction of IFN-α (α-interferon), IL-6 (interleukin-6), IL-10 (interleukin-10), IL-12 (interleukin-12), and IL-23 (interleukin-23). ​​Biochemical studies and gene knockout mice have revealed the important role of TYK2 in immunity. TYK2-deficient mice can grow and reproduce but exhibit multiple immunodeficiency, mainly hypersensitivity to infection and defects in tumor surveillance. Conversely, inhibiting TYK2 can enhance the ability to resist allergic, autoimmune, and inflammatory diseases. In particular, targeting TYK2 appears to be an innovative strategy for treating IL-12, IL-23-, or type I IFN-mediated diseases. The diseases mentioned include, but are not limited to, rheumatoid arthritis, neuroinflammation, multiple sclerosis, lupus, psoriasis, psoriatic arthritis, inflammatory bowel disease, uveitis, sarcoidosis, and cancer (Shaw, M. et al., Proc. Natl. Acad. Sci., USA, 2003, 100, 11594-11599; Ortmann, RA, and Shevach, EMClin. Immunol, 2001, 98, 109-118; Watford et al., Immunol. Rev., 2004, 202:139).

[0005] Given the promising prospects of TYK2-specific inhibitors in the treatment of autoimmune diseases and neurodegenerative diseases, there is an urgent need to develop a novel brain-penetrating TYK2 selective inhibitor with better drugability, stronger efficacy, and higher kinase selectivity. Summary of the Invention

[0006] This invention provides a class of substituted heterocyclic compounds that inhibit, regulate, and / or modulate TYK2 activity for the treatment of neurodegenerative diseases. This invention also provides methods for preparing these compounds, as well as pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention have promising clinical application prospects. Compared with existing similar compounds, the compounds of this invention exhibit better pharmacological activity, pharmacokinetic properties, physicochemical properties, and / or lower toxicity. Specifically, the compounds of this invention show better inhibitory activity and higher TYK2 selectivity, and demonstrate good absorption, high bioavailability, and good blood-brain barrier penetration in in vivo pharmacokinetic studies; furthermore, the compounds of this invention have no cardiotoxicity and good safety. Therefore, the compounds of this invention have superior drug-like properties.

[0007] Specifically:

[0008] On one hand, the present invention relates to a compound of formula (I) or a stereoisomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

[0009]

[0010] in:

[0011] E is either N or CH;

[0012] X is N or CR x ;

[0013] Y is N or CR y ;

[0014] Z is N or CR z ;

[0015] R x R y and R z Each of the following can be independently H, D, F, Cl, Br, I, -OH, -NH2, -NO2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 1-6 Alkylamino;

[0016] R 2 For H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl or heterocyclic group consisting of 3-10 atoms; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The cycloalkyl group and the heterocyclic group consisting of 3-10 atoms are each independently and optionally surrounded by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups;

[0017] R 3 For H, D, C 1-6 Alkyl, C 1-6Halogenated alkyl or C 1-6 Deuterated alkyl groups;

[0018] R 1 For -OR a -C(O)R a -C(O)OR a -NR a R b -NR c C(O)R d -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b -NR a S(O)2R b -C(O)NR a S(O)2R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-12 atoms; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 atoms are each independently and optionally surrounded by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substituted by haloalkoxy groups, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2;

[0019] Each R a R b R c and R dH, D, C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-12 atoms, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 atoms are each independently and optionally surrounded by 1, 2, 3 or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 It is substituted by cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, and substituents such as -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2.

[0020] R 2 For H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl or heterocyclic group consisting of 3-8 atoms; wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl group and the heterocyclic group consisting of 3-8 atoms are each independently and optionally surrounded by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0021] R 3 For H, D, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4Deuterated alkyl groups.

[0022] In other implementations, R 2 The following are not directly related to the preceding text: H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CD3, CH2CD3, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ... The tert-butyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolyl, imidazoalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl groups are each independently and optionally substituted by 1, 2, 3, 4, or 5 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy groups;

[0023] R 3 It can be H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, CD3 or CH2CD3.

[0024] In some implementation schemes, R 1 For -OR a -C(O)R a -C(O)OR a -NR a R b -NR c C(O)R d -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b -NR a S(O)2R b -C(O)NR aS(O)2R b C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-10 atoms; wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally surrounded by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Substituted by haloalkoxy groups, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2;

[0025] Each R a R b R c and R d H, D, C independently 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-10 atoms, wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally surrounded by 1, 2, 3 or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4Hydroxyalkyl, C 3-6 It is substituted by cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, and substituents such as -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2.

[0026] In other implementations, R 1 For -OR a -C(O)R a -C(O)OR a -NR a R b -NR c C(O)R d -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b -NR a S(O)2R b -C(O)NR a S(O)2R bMethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetyl, aziroxy, pyrroleyl Imidazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, azacyclobutyl, pyrrolyl, imidazoalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are each independently and optionally composed of 1, 2, 3, 4, or 5 groups selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, methyl, ethyl, n-propyl Substituents of -methyl, -isopropyl, -n-butyl, -isobutyl, -sec-butyl, -tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2;

[0027] Each R a R b R c and R dIndependently, H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-methylpropenyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, 4,5-dihydrooxazolyl, 5,6-dihydro-4H-pyrrolo[1,2-B]pyrazolyl, phenyl, naphthyl, pyrrolidinyl, pyrazolyl, imidazole, triazolyl Azolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-methylpropenyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, 4,5-dihydrooxazolyl, 5,6-dihydrooxazolyl 4H-pyrrolo[1,2-B]pyrazolyl, phenyl, naphthyl, pyrrolithyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl are each independently and optionally separated by 1, 2, 3, or 4 of the following groups: D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH It is substituted by substituents such as 2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, -CH2OH, -CH2CH2OH, -C(CH3)2OH, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2.

[0028] In some implementation schemes, R x R y and R z Each of the following can be independently H, D, F, Cl, Br, I, -OH, -NH2, -NO2, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or C 1-4 Alkylamino.

[0029] In other implementations, R x R y and R z Each can be independently H, D, F, Cl, Br, I, -OH, -NH2, -NO2, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, -CH2NH2 or -CH2CH2NH2.

[0030] In some embodiments, the compound of the present invention is a compound of formula (Ia) or (Ib), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof of a compound of formula (Ia) or (Ib).

[0031]

[0032] Among them, R 1 R 2 R 3 X, Y, and Z each have the definitions described in this invention.

[0033] On one hand, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), formula (Ia) or formula (Ib) of the present invention, or a stereoisomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

[0034] In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of pharmaceutically acceptable excipients, carriers, and solvents.

[0035] On the other hand, the present invention relates to the use of the compounds or pharmaceutical compositions disclosed herein in the preparation of medicaments for the prevention, treatment, or relief of TYK2-mediated diseases.

[0036] In some embodiments, the TYK2-mediated diseases described in this invention are neurodegenerative diseases, autoimmune diseases, viral diseases, or proliferative diseases.

[0037] In other embodiments, the TYK2-mediated diseases described in this invention include neuroinflammatory diseases, optic neuritis, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, Parkinson's disease, dementia, psoriasis, lupus erythematosus, inflammatory bowel disease, psoriatic arthritis, arthritis, vasculitis, fibrosis, dermatitis, skin aging, encephalitis, lupus nephritis, multiple sclerosis, ALS, myasthenia gravis, mental illnesses, schizophrenia, epilepsy, spinal cord injury, sleep disorders, brain injury, stroke, neuropsychiatric lupus, diabetic encephalopathy, sepsis-associated encephalopathy, central nervous system tumors, Huntington's disease, postoperative neurological syndromes, pain, itching, depression, narcolepsy, hydrocephalus, ankylosing spondylitis, respiratory diseases, diabetes, inflammatory eye diseases, hepatitis, cardiovascular diseases, systemic sclerosis, organ transplantation, alopecia areata, acne, eczema, vitiligo, Sjögren's syndrome, viral inflammation, or cancer.

[0038] On the other hand, the present invention relates to the use of the compounds or pharmaceutical compositions disclosed herein in the preparation of a medicament for inhibiting the activity of JAK.

[0039] In some embodiments, the compounds or pharmaceutical compositions disclosed in this invention are prepared for inhibiting the activity of TYK2.

[0040] In another aspect, the present invention relates to methods for the preparation, separation and purification of compounds contained in formula (I), formula (Ia) or formula (Ib).

[0041] Biological test results show that the compounds provided by this invention can serve as good JAK inhibitors, especially as TYK2 inhibitors.

[0042] Any embodiments of any aspect of the present invention may be combined with other embodiments, provided that they do not contradict each other. Furthermore, any technical feature in any embodiment of any aspect of the present invention may be applied to the same technical feature in other embodiments, provided that they do not contradict each other.

[0043] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below.

[0044] Detailed Description of the Invention

[0045] Definitions and general terms

[0046] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the appended documents, patents, and similar materials differ from or contradict the invention (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), the invention shall prevail.

[0047] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0048] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0049] Unless otherwise stated, the following definitions as used in this invention shall apply. For the purposes of this invention, chemical elements are consistent with the periodic table (CAS edition) and the Handbook of Chemistry and Physics, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0050] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0051] Unless otherwise stated or there is an obvious conflict in the context, the articles “a,” “an,” and “described” as used in this invention are intended to include “at least one” or “one or more.” Therefore, these articles as used in this invention refer to articles for one or more (i.e., at least one) objects. For example, “a component” refers to one or more components, meaning that more than one component may be considered for use or employed in the embodiments described.

[0052] As used in this invention, the term "test subject" refers to an animal. Typically, the animal is a mammal. Test subjects also include, for example, primates (e.g., humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the test subject is a primate. In other embodiments, the test subject is a human.

[0053] As used in this invention, the term "patient" refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a person.

[0054] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0055] "Stereoisomers" are compounds that have the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), and hindered isomers, etc.

[0056] "Chirality" refers to molecules that have the property that they cannot be superimposed on their mirror image; while "chirality" refers to molecules that can be superimposed on their mirror image.

[0057] "Enantiomers" refer to two non-overlapping but mirror-image isomers of a compound.

[0058] A diastereomer is a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0059] The stereochemical definitions and rules used in this invention generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994.

[0060] Many organic compounds exist in an optically active form, meaning they possess the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols used to specify the plane-polarized light rotation caused by the compound, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

[0061] Any asymmetric atom (e.g., carbon, etc.) in the compounds disclosed in this invention can exist in a racemic or enantiomerically enriched form, such as in (R)-, (S)-, or (R,S)- configurations. In some embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)- configuration.

[0062] Depending on the choice of starting materials and methods, the compounds of this invention can exist as one or a mixture of possible isomers, such as racemic mixtures and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be E or Z configurations; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be cis or trans configurations.

[0063] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0064] Racemates of any resulting end product or intermediate can be separated into optical enantiomers using known methods, such as by separating salts of their diastereomers. Racemate products can also be separated by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed.Robert E.Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G.Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0065] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridin-4-ol and pyridin-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0066] As described in this invention, the compounds of this invention may optionally be substituted with one or more substituents, such as the general formula compounds above, or as the specific examples, subclasses, and a class of compounds included in this invention.

[0067] Generally, the term "substituted" means that one or more substituted hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, a substituted group may have one substituent at each substituted position of the group. When more than one position in a given structural formula can be replaced by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions.

[0068] The terms “optional” or “optionally” mean that the event or situation described below may but does not have to occur, including situations in which the event or situation may or may not occur. For example, “optionally alkyl-substituted heterocyclic group” means that the alkyl group may but does not have to be present, including scenarios where the heterocyclic group is substituted with an alkyl group and scenarios where the heterocyclic group is not substituted with an alkyl group.

[0069] The term "unsubstituted" means that the specified group does not have substituents.

[0070] The term "optionally replaced by" can be used interchangeably with the term "unsubstituted or replaced by," meaning that the structure is unsubstituted or replaced by one or more substituents as described in this invention.

[0071] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each…independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0072] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, the invention includes every independent secondary combination of the various members of these group types and scopes. For example, the term "C..." 1-6 "Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0073] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0074] As used in this invention, the term "alkyl" or "alkyl group" refers to a saturated straight-chain or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be substituted by one or more substituents described in this invention. Unless otherwise specified, the alkyl group contains 1 to 20 carbon atoms. In some embodiments, the alkyl group contains 1 to 12 carbon atoms; in other embodiments, the alkyl group contains 2 to 12 carbon atoms; in still other embodiments, the alkyl group contains 1 to 6 carbon atoms; in yet other embodiments, the alkyl group contains 2 to 6 carbon atoms; in still other embodiments, the alkyl group contains 1 to 4 carbon atoms; and in still other embodiments, the alkyl group contains 1 to 3 carbon atoms.

[0075] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)2CH2CH3) 3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 2,2-dimethylpropyl (neopentyl,-CH2C(CH3)2CH3), 3-methyl-1-butyl (-CH2CH2C) H(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH 3) CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc.

[0076] The term "alkoxy group" indicates that an alkyl group is attached to the remainder of the molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; and in still other embodiments, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in this invention.

[0077] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2- Propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (n-pentoxy, -OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc.

[0078] The terms "hydroxyalkyl" and "hydroxyalkoxy" indicate that an alkyl or alkoxy group is replaced by one or more hydroxyl substituents. "Hydroxyalkyl" and "hydroxyalkyl" can be used interchangeably. Examples include, but are not limited to, hydroxymethyl (-CH2OH), hydroxyethyl (-CH2CH2OH, -CH(OH)CH3), and hydroxypropyl (-CH2CH2CH2OH, -CH2CH(OH)CH3). 3, -CH(OH)CH2CH3), hydroxymethoxy (-OCH2OH), etc.

[0079] The term "haloalkoxy" means that the alkoxy group is replaced by one or more halogen atoms, wherein the alkoxy group has the meaning described in this invention; such examples include, but are not limited to, difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3), etc.

[0080] The term "haloalkyl" indicates that an alkyl group is replaced by one or more halogen atoms, wherein the alkyl group has the meaning described herein. Some embodiments include a haloalkyl group containing 1-12 carbon atoms; other embodiments include a haloalkyl group containing 1-10 carbon atoms; other embodiments include a haloalkyl group containing 1-8 carbon atoms; other embodiments include a haloalkyl group containing 1-6 carbon atoms; other embodiments include a haloalkyl group containing 1-4 carbon atoms; and other embodiments include a haloalkyl group containing 1-3 carbon atoms. Such examples include, but are not limited to, difluoromethyl (-CHF2), trifluoromethyl (-CF3), 2,2-difluoroethyl (-CH2CHF2), 2,2,2-trifluoroethyl (-CH2CF3), etc.

[0081] The terms "alkylamino" and "alkanoamino" are used interchangeably, including "N-alkanoamino" and "N,N-dialkylamino," wherein the amino group is independently substituted by one or two alkyl substituents. In some embodiments, the alkanoamino group is one or two C14 groups. 1-12 The alkyl group is attached to a lower-order alkylamino group formed on the nitrogen atom. In other embodiments, the alkylamino group has one or two C atoms. 1-6 The alkyl group is attached to a lower-order alkylamino group formed on the nitrogen atom. In other embodiments, the alkylamino group has one or two C atoms. 1-4 The alkyl group is attached to a lower-order alkylamino group formed on the nitrogen atom. In some other embodiments, the alkylamino group has one or two carbon atoms. 1-3 An alkyl group is attached to a nitrogen atom to form a lower-order alkylamino group. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and examples of alkylamino groups include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, etc.

[0082] The term "carbocyclic" or "carbocyclic" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic, or tricyclic system containing 3 to 12 carbon atoms. Carbocyclic groups include spirobicyclic, fused, and bridged carbocyclic groups. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloynyl groups. Further examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and so on.

[0083] The term "cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic system containing 3-12 carbon atoms. In some embodiments, the cycloalkyl group contains 3-12 carbon atoms; in other embodiments, it contains 3-8 carbon atoms; in still other embodiments, it contains 4-7 carbon atoms; and in yet another embodiment, it contains 3-6 carbon atoms. In some embodiments, the cycloalkyl group contains 7-12 carbon atoms, i.e., C64-C ... 7-12 cycloalkyl groups, which further contain C 7-12 Spirobicycloalkyl, C 7-12 Fused bicycloalkyl and C 7-12 Bridged bicycloalkyl; in other embodiments, the cycloalkyl group is composed of 8-11 carbon atoms, i.e., C164-C ... 8-11 cycloalkyl groups, which further contain C 8-11 Spirobicycloalkyl, C 8-11 Fused bicycloalkyl and C 8-11 Bridged ring bicycloalkyl. In some embodiments, C 3-6 Cycloalkyl groups specifically refer to rings containing 3-6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl groups may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0084] The terms "heterocyclic group" and "heterocycle" are used interchangeably herein to refer to a monovalent or polyvalent, saturated or partially unsaturated, non-aromatic monocyclic, bicyclic, or tricyclic system comprising 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise stated, the heterocyclic group can be carbonyl or nitrogenyl, and the -CH2- group may optionally be replaced by -C(=O)-. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. Heterocyclic groups include saturated heterocyclic groups (i.e., heterocyclic alkyl groups) and partially unsaturated heterocyclic groups. In some embodiments, the heterocyclic group is a heterocyclic group consisting of 3 to 8 atoms; in other embodiments, the heterocyclic group is a heterocyclic group consisting of 3 to 6 atoms.

[0085] Examples of heterocyclic groups include, but are not limited to: ethylene oxide, azirrobutyl, oxacyclobutyl, thioheterobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, tetrahydrothiopyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxaneyl, dithiaalkyl, thiaalkyl, homopiperazineyl, homopiperidinyl, oxacycloheptyl, thioheptanyl, oxacyclohept ... Matrix (e.g., 1,4-oxo-nitrogenous compounds) basal, 1,2-oxo-nitrogen (base), diaza alkyl groups (e.g., 1,4-diaza) 1,2-diaza (base), dioxane Matrix (e.g., 1,4-dioxane) 1,2-dioxane (Base), sulfur nitrogen Matrix (such as 1,4-thiazolidinediones) 1,2-thiazolyl (e.g., indolinyl), 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxonyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, 2-azaspiro[4.4]nonyl, 2-oxaspiro[3.3]heptyl, 1,6-dioxaspiro[4.4]nonyl, 2-azaspiro[4.5]decyl, 8-azaspiro[4.5]decyl, 7-azaspiro[4.5]decyl, 3-azaspiro[5.5]undecyl, 2-azaspiro[5.5]undecyl, octahydro-1H-isoindolyl, octahydrocyclopentano[c]pyrroliyl, hexahydrofurano[3,2-b]furanyl, dihydro-4H-pyrrolo[1,2-B]pyrazolyl and dodecahydroisoquinolinyl, etc. Examples of heterocyclic groups where the -CH2- group is replaced by -C(=O)- include, but are not limited to, 1,1-dioxoisothiazolidinone-2-yl, pyrrolidone-2-yl, imidazolidinone-1-yl, oxazolidinone-2-yl, 2-oxopyrrolyl, oxo-1,3-thiazolidinyl, 2-piperidinone, and 3,5-dioxopiperidinyl. Examples of heterocyclic groups where the sulfur atom is oxidized include, but are not limited to, sulfolane, 1,1-dioxothiomorpholinyl, 1,1-dioxotetrahydrothiophene, and 1,1-dioxotetrahydro-2H-thiaranyl, etc. The heterocyclic groups may optionally be replaced by one or more substituents described in this invention.

[0086] The term "heteroatom" refers to O, S, N, P, and Si, including any oxidation state of N, S, and P; primary, secondary, tertiary amines, and quaternary ammonium salts; or forms in which the hydrogen atom on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrole), NH (like NH in pyrroleyl), or NR (like NR in N-substituted pyrroleyl, where R is a substituent as described in this invention).

[0087] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0088] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14, 6-12, or 6-10 ring atoms, wherein at least one ring system is aromatic, and each ring system comprises a ring of 3-7 atoms with one or more connection points attached to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups may include phenyl, naphthyl, and anthracene. The aryl group may be optionally and independently substituted by one or more substituents described in this invention.

[0089] The term "heteroaryl" refers to an aromatic monocyclic, bicyclic, or tricyclic system containing 5-12, 5-10, or 5-6 ring atoms, wherein at least one ring system contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and each ring system comprises a ring of 5-7 atoms and has one or more connection points attached to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound".

[0090] Examples of heteroaryl groups include, but are by no means limited to: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (e.g., 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), indazoleyl (e.g., 3-indazoleyl, 4-indazoleyl, 5-indazoleyl, 6-indazoleyl, 7-indazoleyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[4,3-c]pyridyl, pyrazolo[3,4-b]pyridyl, Pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-c]pyrimidinyl, 1H-benzo[d][1,2,3]triazolyl, 3H-imidazo[4,5-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-benzo[d]imidazolyl, 1H-pyrazolo[3,2-b]pyridinyl, [1,2,4]triazolo[1,5-a] Pyridyl, purine, furanyl (e.g., 2-furanyl, 3-furanyl), imidazole (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrroleyl (e.g., 1-pyrroleyl, 2-pyrroleyl, 3-pyrroleyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridinoneyl, pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrimidinoneyl, pyrimidinidoneyl, pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g., 2-pyridyl...) Phosphatidyl, 3-pyrazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), thiophene (e.g., 2-thiophene, 3-thiophene), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl), pyrazolone, isothiazolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl), 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, and 1,3,5-triazinyl, etc.

[0091] As used in this invention, the term "prodrug" refers to the conversion of a compound into a compound represented by formula (I), (Ia), or (Ib) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0092] "Metabolic products" refer to the products obtained from the metabolism of a specific compound or its salt in vivo. The metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0093] As used in this invention, "pharmaceutically acceptable salts" refers to the organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reactions with amino groups, such as hydrochlorides, hydrobromic acids, phosphates, sulfates, and perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or these salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucono-p-gluconate, glyceryl phosphate, gluconate, hemisulfate, heptanate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by means of appropriate bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + Salts of (C1-C4 alkyl)4. This invention also contemplates quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations resistant to the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0094] In this invention, "solvent" refers to an association formed by one or more solvent molecules with the compound of this invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0095] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters) or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0096] As used in this invention, "inflammatory disease" refers to any disease, disorder, or symptom resulting from excessive or uncontrolled inflammatory response, including excessive inflammatory symptoms, host tissue damage, or loss of tissue function. "Inflammatory disease" also refers to a pathological state mediated by leukocyte influx and / or neutrophil chemotaxis.

[0097] As used in this invention, "inflammation" refers to a local protective response caused by tissue damage or destruction, which serves to destroy, dilute, or isolate harmful substances and damaged tissue. Inflammation is significantly associated with leukocyte influx and / or neutrophil chemotaxis. Inflammation can arise from pathogenic organism and viral infection, as well as non-infectious pathways such as trauma or reperfusion after myocardial infarction or stroke, immune responses to foreign antigens, and autoimmune responses. Therefore, inflammatory diseases that can be treated with the compounds disclosed in this invention include diseases related to both specific and non-specific defense system responses.

[0098] "Specific defense system" refers to the response of components of the immune system to the presence of specific antigens. Examples of inflammation arising from a specific defense system response include classical responses to foreign antigens, autoimmune diseases, and delayed-type hypersensitivity responses (mediated by T cells). Other examples of inflammatory responses in the specific defense system include chronic inflammatory diseases, rejection of transplanted solid tissues and organs (such as kidney and bone marrow transplants), and graft-versus-host disease (GVHD).

[0099] As used in this invention, "autoimmune disease" refers to any collection of diseases involving tissue damage related to humoral or cellular responses to the body's own components.

[0100] As used in this invention, "allergy" refers to any symptom of an allergic reaction, tissue damage, or loss of tissue function. As used in this invention, "arthritis disease" refers to any disease characterized by inflammatory lesions of the arthritis attributable to various etiologies. As used in this invention, "dermatitis" refers to any of the large family of skin diseases characterized by inflammation of the skin attributable to various etiologies. As used in this invention, "transplant rejection" refers to any immune response against transplanted tissue, such as organs or cells (e.g., bone marrow), characterized by loss of function of the transplanted or surrounding tissue, pain, swelling, leukocytosis, and thrombocytopenia. The treatment methods of this invention include methods for treating diseases associated with inflammatory cell activation.

[0101] Description of the compounds of the present invention

[0102] This invention discloses a novel class of compounds that can be used as JAK inhibitors to treat diseases associated with JAK activity, particularly those associated with TYK2 activity, including neurodegenerative diseases, autoimmune diseases, viral diseases, or proliferative diseases.

[0103] On one hand, the present invention relates to a compound as shown in formula (I), or a stereoisomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof of a compound shown in formula (I).

[0104]

[0105] Among them, each R 1 R 2 R 3 E, X, Y, and Z all have the meanings described in this invention.

[0106] In some implementations, E is N or CH.

[0107] In some implementations, X is N or CR x ;where R x It has the meaning described in this invention.

[0108] In some implementations, Y is N or CR y ;where R y It has the meaning described in this invention.

[0109] In some implementations, Z is N or CR z ;where R z It has the meaning described in this invention.

[0110] In some implementation schemes, R x R y and R zEach of the following can be independently H, D, F, Cl, Br, I, -OH, -NH2, -NO2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 1-6 Alkylamino.

[0111] In some implementation schemes, R x R y and R z Each of the following can be independently H, D, F, Cl, Br, I, -OH, -NH2, -NO2, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or C 1-4 Alkylamino.

[0112] In other implementations, R x R y and R z Each can be independently H, D, F, Cl, Br, I, -OH, -NH2, -NO2, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, -CH2NH2 or -CH2CH2NH2.

[0113] In some implementation schemes, R 2 For H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl or heterocyclic group consisting of 3-10 atoms; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The cycloalkyl group and the heterocyclic group consisting of 3-10 atoms are each independently and optionally surrounded by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups;

[0114] In some implementation schemes, R 2 For H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl or heterocyclic group consisting of 3-8 atoms; wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl group and the heterocyclic group consisting of 3-8 atoms are each independently and optionally surrounded by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are replaced.

[0115] In other implementations, R 2 The following are not directly related to the preceding text: H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CD3, CH2CD3, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ... The tert-butyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolyl, imidazoalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl groups are each independently and optionally substituted by 1, 2, 3, 4, or 5 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy groups.

[0116] In some implementation schemes, R 3 For H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C1-6 Deuterated alkyl groups.

[0117] In some implementation schemes, R 3 For H, D, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Deuterated alkyl groups.

[0118] In other implementations, R 3 It can be H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, CD3 or CH2CD3.

[0119] In some implementation schemes, R 1 For -OR a -C(O)R a -C(O)OR a -NR a R b -NR c C(O)R d -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b -NR a S(O)2R b -C(O)NR a S(O)2R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-12 atoms; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C 6-10The aryl group and the heteroaryl group consisting of 5-12 atoms are each independently and optionally surrounded by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substituents of haloalkoxy groups, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2; wherein R a R b R c and R d It has the meaning described in this invention.

[0120] In some implementation schemes, R 1 For -OR a -C(O)R a -C(O)OR a -NR a R b -NR c C(O)R d -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b -NR a S(O)2R b -C(O)NR a S(O)2R b C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-10 atoms; wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally surrounded by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Substituents of haloalkoxy groups, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2; wherein R a R b R c and R d It has the meaning described in this invention.

[0121] In other implementations, R 1 For -OR a -C(O)R a -C(O)OR a -NR a R b -NR c C(O)R d -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b -NR a S(O)2R b -C(O)NR a S(O)2R bMethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetyl, aziroxy, pyrroleyl Imidazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, cyclopropenyl Cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine, pyrrolyl, imidazoalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are each independently and optionally surrounded by 1, 2, 3, 4, or 5 groups selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, methyl, ethyl, n-propyl, The substituents of isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2 are substituted; wherein R a R b R c and R d It has the meaning described in this invention.

[0122] In some implementation schemes, R a and R b H, D, C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-12 atoms, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 3-8 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 atoms are each independently and optionally surrounded by 1, 2, 3 or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 It is substituted by cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, and substituents such as -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2.

[0123] In some implementation schemes, R a and R b H, D, C independently 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-10 atoms, wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally surrounded by 1, 2, 3 or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkyl, C 3-6 It is substituted by cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, and substituents such as -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2.

[0124] In other implementations, R a and R bIndependently, H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-methylpropenyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, 4,5-dihydrooxazolyl, 5,6-dihydro-4H-pyrrolo[1,2-B]pyrazolyl, phenyl, naphthyl, pyrrolidinyl, pyrazolyl, imidazole, triazolyl Azolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-methylpropenyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, 4,5-dihydrooxazolyl, 5,6-dihydrooxazolyl 4H-pyrrolo[1,2-B]pyrazolyl, phenyl, naphthyl, pyrrolithyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl are each independently and optionally separated by 1, 2, 3, or 4 of the following groups: D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH It is substituted by substituents such as 2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, -CH2OH, -CH2CH2OH, -C(CH3)2OH, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2.

[0125] In some implementation schemes, R c and R d H, D, C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-12 atoms, wherein the C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 atoms are each independently and optionally surrounded by 1, 2, 3 or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 It is substituted by cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, and substituents such as -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2.

[0126] In some implementation schemes, R c and R d H, D, C independently 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-10 atoms, wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally surrounded by 1, 2, 3 or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkyl, C 3-6 It is substituted by cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, and substituents such as -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2.

[0127] In other implementations, R c and R dIndependently, H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-methylpropenyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, 4,5-dihydrooxazolyl, 5,6-dihydro-4H-pyrrolo[1,2-B]pyrazolyl, phenyl, naphthyl, pyrrolidinyl, pyrazolyl, imidazole, triazolyl Azolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-methylpropenyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, 4,5-dihydrooxazolyl, 5,6-dihydrooxazolyl 4H-pyrrolo[1,2-B]pyrazolyl, phenyl, naphthyl, pyrrolithyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl are each independently and optionally separated by 1, 2, 3, or 4 of the following groups: D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH It is substituted by substituents such as 2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, -CH2OH, -CH2CH2OH, -C(CH3)2OH, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2.

[0128] In some embodiments, the compound of the present invention is a compound of formula (Ia), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof of a compound of formula (Ia).

[0129]

[0130] Among them, R 1 R 2 R3 X, Y, and Z each have the definitions described in this invention.

[0131] In some embodiments, the compound of the present invention is a compound of formula (Ib), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof of a compound of formula (Ib).

[0132]

[0133] Among them, R 1 R 2 R 3 X, Y, and Z each have the definitions described in this invention.

[0134] On the other hand, the present invention relates to a compound or its stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs, but is by no means limited to:

[0135]

[0136]

[0137] Unless otherwise stated, stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs of the compounds shown in formula (I), (Ia), or (Ib) are included within the scope of this invention.

[0138] The compounds disclosed in this invention may contain asymmetric or chiral centers, and therefore may exist in different stereoisomeric forms. This invention aims to include all stereoisomeric forms of the compounds shown in formula (I), (Ia), or (Ib), including but not limited to diastereomers, enantiomers, transisomers, and geometric (or conformational) isomers, as well as mixtures thereof such as racemic mixtures, as part of this invention.

[0139] In the structures disclosed in this invention, when the stereochemistry of any particular chiral atom is not specified, all stereoisomers of that structure are considered within the scope of this invention and are included in this invention as disclosed compounds. When the stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of that structure are thus clearly defined.

[0140] The compounds shown in formula (I), formula (Ia) or formula (Ib) may exist in different tautomer forms, and all such tautomers, as described in this invention, are included within the scope of this invention.

[0141] The compounds shown in formula (I), (Ia), or (Ib) may be present in the form of salts. In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with other components comprising the formulation and / or the mammals treated therein. In other embodiments, the salt is not necessarily a pharmaceutically acceptable salt and may be an intermediate used for the preparation and / or purification of the compounds shown in formula (I), (Ia), or (Ib) and / or for the isolation of enantiomers of the compounds shown in formula (I), (Ia), or (Ib).

[0142] Pharmaceutically usable acid addition salts can be formed by reacting compounds of formula (I), (Ia), or (Ib) with inorganic or organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromates, bicarbonates / carbonates, bisulfates / sulfates, camphorsulfonates, chlorides / hydrochlorides, theophylline salts, citrates, ethanedisulfonates, fumarates, glucohepanoates, glucuronates, glucuronates, hippurates, hydroiodates / iodides. Compounds, hydroxyethyl sulfonates, lactates, lacturonates, lauryl sulfates, malates, maleates, malonates, mandelates, methanesulfonates, methyl sulfates, naphthates, naphthalene sulfonates, nicotinates, nitrates, stearates, oleates, oxalates, palmitates, pyrates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalactosates, propions, stearates, succinates, sulfosalicylates, tartrates, toluenesulfonates, and trifluoroacetates.

[0143] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0144] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc.

[0145] Pharmaceutical alkali addition salts can form with inorganic and organic bases.

[0146] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the periodic table. In some embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0147] Organic bases from which salts can be derived include primary, secondary, and tertiary amines. Substituted amines include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Some organic amines include, for example, isopropylamine, benzathine penicillin, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0148] The pharmaceutically acceptable salts of the present invention can be synthesized using conventional chemical methods from a parent compound, a basic or acidic moiety. Generally, these salts can be prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. These reactions are typically carried out in water or an organic solvent or a mixture thereof. Generally, in suitable cases, a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is required. Other suitable salts can be listed, for example, in “Remington’s Pharmaceutical Sciences,” 20th edition, Mack Publishing Company, Easton, Pa., (1985); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use,” Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0149] Furthermore, the compounds disclosed in this invention, including their salts, can also be obtained in their hydrated form or in the form containing their solvents (e.g., ethanol, DMSO, etc.) for their crystallization. The compounds disclosed in this invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, this invention is intended to include both solvated and unsolvated forms.

[0150] Any structural formulas provided in this invention are intended to represent both the unenriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures described by the general formulas provided in this invention, except that one or more atoms are replaced by atoms having a chosen atomic weight or mass number. Exemplary isotopes that may be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 15 N、17 O、 18 O、 18 F, 32 P, 35 S, 36 Cl and 125 I.

[0151] On the other hand, the compounds described in this invention include isotopically enriched compounds as defined in this invention, for example, compounds containing radioactive isotopes, such as... 3 H, 14 C and 18 Those compounds of F, or those containing non-radioactive isotopes, such as 2 H and 13 C. Compounds enriched by this type of isotope can be used for metabolic studies (using...) 14 C) Reaction kinetic studies (using, for example) 2 H or 3 H) Detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) which includes the determination of drug or substrate tissue distribution, may be used in the patient's radiotherapy. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. The isotopically enriched compounds of formula (I), (Ia), or (Ib) can be prepared using conventional techniques familiar to those skilled in the art, or by replacing the previously used unlabeled reagent with a suitable isotopic labeling reagent, as described in the examples and preparation processes of this invention.

[0152] In addition, heavier isotopes, especially deuterium (i.e., 2Substitution with H or D can provide certain therapeutic advantages resulting from increased metabolic stability. For example, this may lead to an increased half-life in vivo, reduced dose requirement, or improved therapeutic index. It should be understood that deuterium in this invention is considered as a substituent in the compounds represented by formula (I), (Ia), or (Ib). The concentration of such heavier isotopes, particularly deuterium, can be defined using an isotope enrichment factor. As used in this invention, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of the specified isotope and its native abundance. If the substituent of the compound of the present invention is designated as deuterium, the compound has an isotopic enrichment factor of at least 3500 (52.5% deuterium doping at each designated deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping) with respect to each designated deuterium atom. The pharmaceutically usable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, such as D2O, acetone-d6, DMSO-d6.

[0153] On the other hand, the present invention relates to intermediates for preparing compounds of formula (I), formula (Ia) or formula (Ib).

[0154] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I), formula (Ia) or formula (Ib).

[0155] On the other hand, the present invention provides a pharmaceutical composition comprising the compounds of the present invention. In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of pharmaceutically acceptable excipients, excipients, carriers, and solvents. In other embodiments, the pharmaceutical composition may be a liquid, solid, semi-solid, gel, or spray formulation.

[0156] On the other hand, the present invention relates to methods for treating diseases or disorders regulated by JAK, the treatment method comprising administering an effective amount of the disclosed compound or pharmaceutical composition to a mammal. In some embodiments, the JAK is TYK2. In some implementations, the disease or disorder is selected from neuroinflammatory diseases, optic neuritis, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, Parkinson's disease, dementia, psoriasis, lupus erythematosus, inflammatory bowel disease, psoriatic arthritis, arthritis, vasculitis, fibrosis, dermatitis, skin aging, encephalitis, lupus nephritis, multiple sclerosis, ALS, myasthenia gravis, mental illness, schizophrenia, epilepsy, spinal cord injury, sleep disorder, brain injury, stroke, neuropsychiatric lupus, diabetic encephalopathy, sepsis-associated encephalopathy, central nervous system tumors, Huntington's disease, postoperative neurological syndrome, pain, itching, depression, somnolencephaly, hydrocephalus, ankylosing spondylitis, respiratory diseases, diabetes, inflammatory eye diseases, hepatitis, cardiovascular diseases, systemic sclerosis, organ transplantation, alopecia areata, acne, eczema, vitiligo, Sjögren's syndrome, viral inflammation, or cancer.

[0157] On the other hand, this invention relates to the treatment of diseases or disorders using the compounds or pharmaceutical compositions of the present invention disclosed herein, said diseases or disorders being selected from neuroinflammatory diseases, optic neuritis, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, Parkinson's disease, dementia, psoriasis, lupus erythematosus, inflammatory bowel disease, psoriatic arthritis, arthritis, vasculitis, fibrosis, dermatitis, skin aging, encephalitis, lupus nephritis, multiple sclerosis, ALS, myasthenia gravis, mental illnesses, schizophrenia, epilepsy, spinal cord injury, sleep disorders, brain injury, stroke, neuropsychiatric lupus, diabetic encephalopathy, sepsis-associated encephalopathy, central nervous system tumors, Huntington's disease, postoperative neurological syndromes, pain, itching, depression, narcolepsy, hydrocephalus, ankylosing spondylitis, respiratory diseases, diabetes, inflammatory eye diseases, hepatitis, cardiovascular diseases, systemic sclerosis, organ transplantation, alopecia areata, acne, eczema, vitiligo, Sjögren's syndrome, viral inflammation, or cancer.

[0158] On the other hand, this invention relates to the use of the compounds or pharmaceutical compositions disclosed in this invention in the preparation of remedies for treating diseases or disorders, said diseases being selected from neuroinflammatory diseases, optic neuritis, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, Parkinson's disease, dementia, psoriasis, lupus erythematosus, inflammatory bowel disease, psoriatic arthritis, arthritis, vasculitis, fibrosis, dermatitis, skin aging, encephalitis, lupus nephritis, multiple sclerosis, ALS, myasthenia gravis, mental illnesses, schizophrenia, epilepsy, spinal cord injury, sleep disorders, brain injury, stroke, neuropsychiatric lupus, diabetic encephalopathy, sepsis-associated encephalopathy, central nervous system tumors, Huntington's disease, postoperative neurological syndromes, pain, itching, depression, somnolencephaly, hydrocephalus, ankylosing spondylitis, respiratory diseases, diabetes, inflammatory eye diseases, hepatitis, cardiovascular diseases, systemic sclerosis, organ transplantation, alopecia areata, acne, eczema, vitiligo, Sjögren's syndrome, viral inflammation, or cancer.

[0159] On the other hand, the present invention relates to the use of the compounds or pharmaceutical compositions of the present invention disclosed herein for the preparation of a medicament for inhibiting the activity of TYK2.

[0160] Pharmaceutical compositions, formulations and administration of the compounds of the present invention

[0161] This invention provides a pharmaceutical composition comprising the compounds disclosed herein, or the compounds listed in the examples; and at least one of pharmaceutically acceptable excipients, carriers, and solvents. The amount of the compound in the pharmaceutical composition disclosed herein refers to an amount that can be effectively detected to inhibit protein kinases in a biological sample or patient.

[0162] It should also be recognized that certain compounds of the present invention may be present in free form for therapeutic purposes, or, if appropriate, in the form of their pharmaceutically acceptable derivatives. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of these esters, or any other adducts or derivatives that, when administered to a patient in need, directly or indirectly provide the compounds of the present invention or their metabolites or residues.

[0163] The pharmaceutical compositions disclosed in this invention can be prepared and packaged in bulk form, wherein a safe and effective amount of the compound represented by formula (I), formula (Ia), or formula (Ib) can be extracted and then administered to the patient in powder or syrup form. Alternatively, the pharmaceutical compositions disclosed in this invention can be prepared and packaged in unit dosage forms, wherein each physically discrete unit contains a safe and effective amount of the compound represented by formula (I), formula (Ia), or formula (Ib).

[0164] As used in this invention, "pharmaceuticalally acceptable excipient" refers to a pharmaceutically acceptable material, mixture, or solvent related to the consistency of the dosage form or pharmaceutical composition. Each excipient must be compatible with the other components of the pharmaceutical composition when mixed to avoid interactions that would significantly reduce the efficacy of the disclosed compounds when administered to a patient, and interactions that would result in a pharmaceutically unacceptable pharmaceutical composition. Furthermore, each excipient must be pharmaceutically acceptable, for example, having sufficiently high purity.

[0165] Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form chosen. Furthermore, pharmaceutically acceptable excipients can be selected based on their specific function in the composition. For example, certain pharmaceutically acceptable excipients can be selected that contribute to the production of a uniform dosage form. Certain pharmaceutically acceptable excipients can be selected that contribute to the production of a stable dosage form. Certain pharmaceutically acceptable excipients can be selected that facilitate the transport or delivery of the compounds disclosed in this invention from one organ or part of the body to another organ or part of the body during patient administration. Certain pharmaceutically acceptable excipients can be selected that enhance patient compliance.

[0166] Suitable pharmaceutically acceptable excipients include the following types: diluents, fillers, binders, disintegrants, lubricants, flow aids, granulators, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffers. Those skilled in the art will recognize that some pharmaceutically acceptable excipients can provide more than one function and offer alternative functions, depending on the quantity of that excipient present in the formulation and the other excipients present in the formulation.

[0167] Those skilled in the art possess the knowledge and skills to select appropriate amounts of suitable pharmaceutically acceptable excipients for use in this invention. Furthermore, numerous resources are available to those skilled in the art describing pharmaceutically acceptable excipients and for selecting suitable ones. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0168] Various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation are disclosed in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York. The contents of these documents are incorporated herein by reference. Except for any commonly used carriers that are incompatible with the compounds disclosed herein due to any undesirable biological effects or harmful interactions with any other component of a pharmaceutically acceptable composition, interest in their use is within the scope of this invention.

[0169] The pharmaceutical compositions disclosed in this invention are prepared using techniques and methods known to those skilled in the art. Descriptions of some commonly used methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0170] Therefore, on the other hand, the present invention relates to a process for preparing a pharmaceutical composition comprising at least one of the compounds disclosed in this invention and pharmaceutically acceptable excipients, carriers, and solvents, wherein the process comprises mixing the various components. Pharmaceutical compositions comprising the compounds disclosed in this invention can be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

[0171] The compounds disclosed in this invention are generally formulated into dosage forms suitable for administration to patients via desired routes. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, sac tablets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, granules, and capsules; (2) parenteral administration, such as sterile solutions, suspensions, and lyophilized powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) inhalation administration, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

[0172] In some embodiments, the compounds disclosed in this invention can be formulated into oral dosage forms. In other embodiments, the compounds disclosed in this invention can be formulated into inhaled dosage forms. In still other embodiments, the compounds disclosed in this invention can be formulated into nasal dosage forms. In yet another embodiment, the compounds disclosed in this invention can be formulated into transdermal dosage forms. In still some embodiments, the compounds disclosed in this invention can be formulated into topical dosage forms.

[0173] The pharmaceutical compositions provided by this invention can be provided as compressed tablets, formulated tablets, chewable tablets, instant tablets, recompressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance resistant to gastric acid but dissolving or disintegrating in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which helps to mask unpleasant tastes or odors and prevents tablet oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings possess the same general properties as sugar coatings. Recompressed tablets are compressed tablets prepared through more than one compression cycle, including multilayer tablets and compressed-coated or dry-coated tablets.

[0174] Tablet dosage forms can be prepared from an active ingredient in powder, crystalline, or granular form, alone or in combination with one or more carriers or excipients described in this invention, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and / or colorants. Flavoring agents and sweeteners are particularly useful in the formation of chewable tablets and lozenges.

[0175] The pharmaceutical compositions provided by this invention can be provided in soft or hard capsules, which can be prepared from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsules, also known as dry-filled capsules (DFC), consist of two segments, one inserted into the other, thus completely encapsulating the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those described in this invention, including methylparaben and propylparaben, and sorbic acid. Liquid, semi-solid, and solid dosage forms provided by this invention can be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patents US Pat. Nos. 4,328,245; 4,409,239, and 4,410,545. The capsules may also be coated as is known to those skilled in the art, thereby improving or maintaining the dissolution of the active ingredients.

[0176] The pharmaceutical compositions provided by this invention can be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems in which one liquid is completely dispersed in another liquid in the form of small spheres; they can be oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers, and preservatives. Suspensions may include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions may include pharmaceutically acceptable acetals, such as di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweet aqueous alcoholic solutions. Syrups are concentrated aqueous solutions of sugars such as sucrose and may also contain preservatives. For liquid dosage forms, for example, solutions in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for precise and convenient administration.

[0177] Other useful liquid and semi-solid dosage forms include, but are not limited to, those comprising the active ingredients provided by this invention and secondary mono- or poly-alkylene glycols, said mono- or poly-alkylene glycols including: 1,2-dimethoxymethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of polyethylene glycol. These formulations may further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[0178] When appropriate, oral dosage units can be microencapsulated. They can also be formulated into compositions for prolonged or sustained release, for example, by coating or embedding particulate material in polymers, waxes, or the like.

[0179] The oral pharmaceutical compositions provided by this invention can also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared using the methods described in US Pat. No. 6,350,458.

[0180] The pharmaceutical compositions provided by this invention can be provided in non-effervescent or effervescent granules and powders for recombination into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and carbon dioxide sources.

[0181] Colorants and flavorings can be used in all of the above dosage forms.

[0182] The compounds disclosed in this invention can also be combined with soluble polymers used as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl asparagine-phenol, or palmitoyl residue-substituted polyoxyethylene polylysine. Furthermore, the compounds disclosed in this invention can be combined with a class of biodegradable polymers used to achieve controlled drug release, such as crosslinked or amphiphilic block copolymers of polylactic acid, polyε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and hydrogels.

[0183] The pharmaceutical compositions provided by this invention can be formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that complement the intended effect.

[0184] The pharmaceutical compositions provided by this invention can be administered parenterally via injection, infusion, or implantation for local or systemic drug delivery. Parenterial delivery methods used in this invention include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

[0185] The pharmaceutical compositions provided by this invention can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for preparation as solutions or suspensions in liquids prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see Remington: The Science and Practice of Pharmacy, ibid.).

[0186] Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous carriers, water-miscible carriers, non-aqueous carriers, antimicrobial agents or preservatives that inhibit microbial growth, stabilizers, solubilizers, isotonic agents, buffers, antioxidants, local anesthetics, suspending agents and dispersants, wetting agents or emulsifiers, complexing agents, multivalent chelating agents or chelating agents, antifreeze agents, cryoprotectants, thickeners, pH adjusters, and inert gases.

[0187] Suitable aqueous carriers include, but are not limited to: water, saline, physiological saline or phosphate-buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic glucose injection, sterile water injection, glucose, and lactated Ringers injection. Non-aqueous carriers include, but are not limited to, non-volatile oils of plant origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, medium-chain triglycerides of coconut oil, and palm seed oil. Water-miscible carriers include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0188] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercury, benzyl alcohol, chlorobutanol, methylparaben and propylparaben, thimerosal, benzalkonium chloride (e.g., benzyl chloride), methylparaben and propylparaben, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol, and glucose. Suitable buffers include, but are not limited to, phosphates and citrates. Suitable antioxidants are those described in this invention, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those described in this invention, including sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers include those described in this invention, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable multivalent chelating agents or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether 7-β-cyclodextrin. CyDex, Lenexa, KS).

[0189] The pharmaceutical compositions provided by this invention can be formulated for single-dose or multiple-dose administration. The single-dose formulations are packaged in ampoules, vials, or syringes. The multiple-dose parenteral formulations must contain an antimicrobial agent at an antibacterial or antifungal concentration. All parenteral formulations must be sterile, as is known and practiced in the art.

[0190] In some embodiments, the pharmaceutical composition is provided as a ready-to-use sterile solution. In other embodiments, the pharmaceutical composition is provided as a sterile, dried, soluble product, including lyophilized powders and subcutaneous tablets, which are reconstituted with a carrier prior to use. In still other embodiments, the pharmaceutical composition is formulated as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is formulated as a sterile, dried, insoluble product reconstituted with a carrier prior to use. In still some embodiments, the pharmaceutical composition is formulated as a ready-to-use sterile emulsion.

[0191] Suitable internal matrices include polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethicone, silicone carbonate copolymer, hydrophilic polymers such as esters of acrylic acid and methacrylate, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

[0192] Suitable external polymeric membranes include polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymer of ethylene chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionically crosslinked polymer polyethylene terephthalate, butyl rubber, chlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol trimer, and ethylene / vinyloxyethanol copolymer.

[0193] On the other hand, the pharmaceutical compositions disclosed in this invention can be formulated into any dosage form suitable for inhalation administration to a patient, such as dry powder, aerosol, suspension, or solution composition. In some embodiments, the pharmaceutical compositions disclosed in this invention can be formulated into a dosage form suitable for inhalation administration to a patient as a dry powder. In still other embodiments, the pharmaceutical compositions disclosed in this invention can be formulated into a dosage form suitable for inhalation administration to a patient via a nebulizer. Dry powder compositions delivered to the lungs by inhalation typically comprise a finely powdered compound disclosed in this invention and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-, and polysaccharides. Fine powders can be prepared, for example, by micronization and grinding. Generally, size-reduced (e.g., micronized) compounds can be prepared by a D0 of about 1 to 10 micrometers. 50 Defined by values ​​(e.g., measured using laser diffraction).

[0194] Aerosols can be formulated by suspending or dissolving the compounds disclosed in this invention in a liquefied propellant. Suitable propellants include chlorinated hydrocarbons, hydrocarbons, and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane, and pentane. Aerosols containing the compounds disclosed in this invention are typically administered to patients via metered-dose inhalers (MDIs). Such devices are known to those skilled in the art.

[0195] Aerosols may contain additional pharmaceutically acceptable excipients that can be used with MDIs, such as surfactants, lubricants, cosolvents, and other excipients, to improve the physical stability of the formulation, improve valve properties, improve solubility, or improve taste.

[0196] Pharmaceutical compositions suitable for transdermal delivery can be formulated as discontinuous patches intended to maintain close contact with the patient's epidermis for an extended period of time. For example, the active ingredient can be delivered from the patch via iontophoresis, as generally described in Pharmaceutical Research, 3(6), 318(1986).

[0197] Pharmaceutical compositions suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. For example, ointments, creams, and gels can be formulated with an aqueous or oil-based matrix and suitable thickeners and / or gelling agents and / or solvents. Such a matrix may include water, and / or oils such as liquid paraffin and vegetable oils (e.g., peanut oil or castor oil), or solvents such as polyethylene glycol. Thickeners and gelling agents used, depending on the nature of the matrix, include soft paraffin, aluminum stearate, cetearyl alcohol, polyethylene glycol, lanolin, beeswax, polycarboxylate, and cellulose derivatives, and / or glyceryl monostearate and / or nonionic emulsifiers.

[0198] Lotions can be formulated with a water or oil base and typically contain one or more emulsifiers, stabilizers, dispersants, suspending agents, or thickeners.

[0199] Topical powders can be shaped in the presence of any suitable powder matrix, such as talc, lactose, or starch. Drops can be formulated with an aqueous or non-aqueous matrix containing one or more dispersants, solubilizers, suspending agents, or preservatives.

[0200] Topical formulations can be administered by applying them to the affected area once or more daily; occlusive dressings covering the skin are preferred. Adhesive reservoir systems allow for continuous or prolonged administration.

[0201] When treating the eyes, or other organs such as the mouth and skin, the composition can be applied as a topical ointment or cream. When formulated as an ointment, the compounds disclosed in this invention can be used with a paraffin or water-soluble ointment base. Alternatively, the compounds disclosed in this invention can be formulated into an ointment with an oil-in-water emulsion base or an oil-in-water emulsion base.

[0202] In some embodiments, the treatment methods disclosed in this invention include administering a safe and effective amount of the compound of this invention or a pharmaceutical composition comprising the compound of this invention to a patient in need. Various embodiments of this invention disclose a method of treating the aforementioned diseases by administering a safe and effective amount of the disclosed compound of this invention or a pharmaceutical composition comprising the disclosed compound of this invention to a patient in need.

[0203] In some embodiments, the compounds disclosed in this invention or pharmaceutical compositions comprising the compounds disclosed in this invention can be administered via any suitable route of administration, including systemic and local administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Local administration includes application to the skin, as well as intraocular, intravaginal, inhalation, and intranasal administration. In one embodiment, the compounds disclosed in this invention or pharmaceutical compositions comprising the compounds disclosed in this invention may be administered orally. In other embodiments, the compounds disclosed in this invention or pharmaceutical compositions comprising the compounds disclosed in this invention may be administered by inhalation. In yet another embodiment, the compounds disclosed in this invention or pharmaceutical compositions comprising the compounds disclosed in this invention may be administered intranasally.

[0204] In some embodiments, the compounds disclosed in this invention or pharmaceutical compositions comprising the compounds disclosed in this invention can be administered once, or, depending on the dosing regimen, administered several times at different time intervals within a specified period. For example, administered once, twice, three times, or four times daily. In some embodiments, administered once daily. In still other embodiments, administered twice daily. Administration can continue until the desired therapeutic effect is achieved or to maintain the desired therapeutic effect indefinitely. A suitable dosing regimen for the compounds disclosed in this invention or pharmaceutical compositions comprising the compounds disclosed in this invention depends on the pharmacokinetic properties of the compound, such as absorption, distribution, and half-life, which can be determined by a person skilled in the art. Furthermore, a suitable dosing regimen for the compounds disclosed in this invention or pharmaceutical compositions comprising the compounds disclosed in this invention includes the duration of administration, depending on factors within the knowledge and experience of a person skilled in the art, such as the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated, the patient's medical history, the nature of concurrent therapies, and the desired therapeutic effect. Such a person skilled in the art should also understand that adjustments to the dosing regimen may be required for individual patient responses to the dosing regimen, or for changes in individual patient needs over time.

[0205] The compounds disclosed in this invention can be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of this invention can be administered separately to other therapeutic agents via the same or different routes of administration, or in the same pharmaceutical composition.

[0206] For individuals weighing approximately 50-70 kg, the pharmaceutical compositions and combinations disclosed in this invention may be in unit dose form containing approximately 1-1000 mg or approximately 1-500 mg of active ingredient. The therapeutically effective amount of the compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition of the individual, the disorder or disease being treated, or its severity. Physicians, clinicians, or veterinarians with common skills can readily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the development of a disorder or disease.

[0207] The dosage characteristics cited above have been demonstrated in in vitro and in vivo studies using advantageous mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues, and specimens. The compounds disclosed herein are intended for in vitro use in solution, such as an aqueous solution, and may also be used in vivo in intestinal, parenteral, and especially intravenous forms, such as suspensions or aqueous solutions.

[0208] In some embodiments, the therapeutically effective dose of the disclosed compounds is from about 0.1 mg to about 2,000 mg per day. The pharmaceutical composition thereof should provide a dose of the compound from about 0.1 mg to about 2,000 mg. In a particular embodiment, the prepared pharmaceutical dosage unit form provides about 1 mg to about 2,000 mg, about 10 mg to about 1,000 mg of the main active ingredient, or a combination of the main ingredients per dosage unit form.

[0209] Furthermore, the compounds disclosed in this invention can be administered as prodrugs. In this invention, a "prodrug" of the disclosed compounds is a functional derivative of the disclosed compounds that, when administered to a patient, ultimately releases in vivo. When the disclosed compounds are administered as prodrugs, those skilled in the art can perform one or more of the following: (a) changing the in vivo onset time of the compound; (b) changing the in vivo duration of action of the compound; (c) changing the in vivo delivery or distribution of the compound; (d) changing the in vivo solubility of the compound; and (e) overcoming the side effects or other difficulties faced by the compound. Typical functional derivatives used to prepare prodrugs include variants of compounds that are chemically or enzymatically cleaved in vivo. These variants, including those for preparing phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.

[0210] Uses of the compounds and pharmaceutical compositions of the present invention

[0211] This invention provides that the compounds and pharmaceutical compositions disclosed herein can be used to treat, prevent or improve diseases or disorders mediated or otherwise affected by TYK2, particularly for the preparation of medicines for the treatment, prevention or improvement of neurodegenerative diseases, autoimmune diseases, viral diseases or proliferative diseases.

[0212] Specifically, the present invention provides a class of compounds disclosed herein or pharmaceutical compositions comprising compounds disclosed herein for treating, preventing or improving diseases or disorders mediated or otherwise affected by inappropriate TYK2 behavior, wherein the diseases or disorders are selected from neurodegenerative diseases, autoimmune diseases, viral diseases or proliferative diseases.

[0213] In some embodiments, such diseases or disorders include, but are not limited to, neuroinflammatory diseases, optic neuritis, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, Parkinson's disease, dementia, psoriasis, lupus erythematosus, inflammatory bowel disease, psoriatic arthritis, arthritis, vasculitis, fibrosis, dermatitis, skin aging, encephalitis, lupus nephritis, multiple sclerosis, ALS, myasthenia gravis, mental illness, schizophrenia, epilepsy, spinal cord injury, sleep disorders, brain injury, stroke, neuropsychiatric lupus, diabetic encephalopathy, sepsis-associated encephalopathy, central nervous system tumors, Huntington's disease, postoperative neurological syndrome, pain, itching, depression, somnolencephaly, hydrocephalus, ankylosing spondylitis, respiratory diseases, diabetes, inflammatory eye diseases, hepatitis, cardiovascular diseases, systemic sclerosis, organ transplantation, alopecia areata, acne, eczema, vitiligo, Sjögren's syndrome, viral inflammation, or cancer.

[0214] In another aspect, the present invention provides a method for treating mammals that suffer from or are at risk of suffering from the diseases disclosed herein, the method comprising administering one or more of the pharmaceutical compositions or compounds disclosed herein at an effective therapeutic dose or an effective preventive dose.

[0215] In one aspect of treatment, the present invention provides a method for treating and / or preventing mammals susceptible to or suffering from TYK2-mediated diseases, the method comprising administering one or more pharmaceutical compositions or compounds disclosed herein at an effective therapeutic or preventative dose. In specific instances, TYK2-mediated diseases are selected from neurodegenerative diseases, autoimmune diseases, viral diseases, or proliferative diseases.

[0216] On the other hand, the present invention provides a class of compounds disclosed herein, or pharmaceutical compositions comprising compounds disclosed herein, for the preparation of medicaments for treating or preventing TYK2-mediated diseases. In specific examples, TYK2-mediated diseases are selected from neurodegenerative diseases, autoimmune diseases, viral diseases, or proliferative diseases.

[0217] In another aspect, the present invention provides methods for treating and / or preventing mammals susceptible to or suffering from neurodegenerative diseases, autoimmune diseases, viral diseases, or proliferative diseases, said methods comprising administering an effective therapeutic or preventative amount of one or more pharmaceutical compositions or compounds disclosed herein. In specific examples, neurodegenerative diseases are selected from, but are not limited to, neuroinflammatory diseases, optic neuritis, neuromyelitis optica, Parkinson's disease, or dementia; inflammatory diseases are selected from, but are not limited to, Crohn's disease and ulcerative colitis; and autoimmune diseases are selected from, but are not limited to, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, atopic dermatitis, vitiligo, lupus nephritis, Sjögren's syndrome, or scleroderma.

[0218] General synthesis steps

[0219] Examples are listed below to describe the present invention. However, it should be understood that the present invention is not limited to these examples, but merely provides a method for practicing the present invention.

[0220] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in formula (I), (Ia), or (Ib). The following reaction schemes and examples are provided to further illustrate the content of the present invention.

[0221] Those skilled in the art will recognize that the chemical reactions described herein can be suitably used to prepare many other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-illustrative compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described herein, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of the present invention.

[0222] The examples described below are in Celsius unless otherwise stated. Reagents were purchased from commodity suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company, and were not further purified before use unless otherwise stated. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Plant, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Plant.

[0223] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether are obtained by reflux drying with metallic sodium. Anhydrous dichloromethane and chloroform are obtained by reflux drying with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide are used after prior drying with anhydrous sodium sulfate.

[0224] The following reactions are generally carried out under positive pressure of nitrogen or argon or with a drying tube attached to an anhydrous solvent (unless otherwise specified). All reaction flasks are sealed with suitable rubber stoppers, and the substrate is injected using a syringe. All glassware is dried.

[0225] The chromatographic column used was a silica gel column. The silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0226] 1 H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer. 1 ¹H NMR spectra are performed using CDCl₃, D₂O, DMSO-d₆, CD₃OD, or acetone-d₆ as solvents (in ppm), with TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are observed, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), ddd (doublet of doublets), dddd (doublet of doublets), dt (doublet of triplets), tt (triplet of triplets). The coupling constant J is expressed in Hertz (Hz).

[0227] The determination conditions for low-resolution mass spectrometry (MS) data were as follows: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1×30mm, 3.5 μm, 6 min, flow rate: 0.6 mL / min; mobile phase: 5%-95% (CH3CN containing 0.1% formic acid) in (H2O containing 0.1% formic acid), electrospray ionization (ESI) at 210 nm / 254 nm, and UV detection.

[0228] Pure compounds were detected using UV at 210 nm / 254 nm using an Agilent 1260 pre-HPLC or a Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80 mm DAC).

[0229] The following abbreviations or English terms are used throughout this invention:

[0230] h hours mL, ml milliliters

[0231] min μL microliters

[0232] CDCl3 (deuterated chloroform) MPa

[0233] DMSO dimethyl sulfoxide M moles per liter

[0234] DMSO-d6-deuterated dimethyl sulfoxide mM mmol / L

[0235] THF tetrahydrofuran (mol)

[0236] H2O water mmol millimole

[0237] DCM, dichloromethane, EDTA, ethylenediaminetetraacetic acid

[0238] DMF HCl hydrochloric acid

[0239] AcOH, NBS, N-bromosuccinimide

[0240] mg mg g g

[0241] n-BuLi n-Butyllithium diox.,dioxane,1,4-dioxane 1,4-dioxane

[0242] LiHMDS bis(trimethylsilylamine) lithium

[0243] Pd(dppf)Cl2 DCM[1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex

[0244] Pd2dba3tris(dibenzylacetone)dipalladium(0)DMAP 4-dimethylaminopyridine

[0245] Rt room temperature overnight, overnight

[0246] hexane (n-hexane)

[0247] XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene

[0248] Xphos-Pd-G2 Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

[0249] The following reaction scheme describes the steps for preparing the compounds of the present invention. Unless otherwise stated, each R... 2 R b X, Y, Z and E have the definitions as described in this invention.

[0250] Synthesis Scheme 1

[0251]

[0252] The compound shown in formula (I) can be prepared by the following synthetic scheme: the compound shown in formula (Ia) reacts with oxalyl chloride and then with potassium monoethyl malonate to obtain the compound shown in formula (Ib); the compound shown in formula (Ib) reacts with deuterated iodomethane to obtain the compound shown in formula (Ic); the compound shown in formula (Ic) reacts under suitable conditions (such as HCl, AcOH, 130℃) to obtain the compound shown in formula (Id); the compound shown in formula (Id) reacts with phosphorus oxychloride to obtain the compound shown in formula (Ie); the compound shown in formula (Ie) reacts with the compound shown in formula (If) under the action of a palladium catalyst to obtain the compound shown in formula (Ig); the compound shown in formula (Ih) reacts with the compound shown in formula (Ii) under the action of a palladium catalyst to obtain the compound shown in formula (Ij); the compound shown in formula (Ij) reacts with the compound shown in formula (Ig) under the action of a palladium catalyst to obtain the compound shown in formula (I).

[0253] Synthesis Scheme 2

[0254]

[0255] The compound shown in formula (I) can be prepared by synthetic scheme two: the compound shown in formula (Ij) reacts with the compound shown in formula (Ie) under the action of a strong base to obtain the compound shown in formula (Ik); the compound shown in formula (Ik) reacts with the compound shown in formula (If) under the action of a palladium catalyst to obtain the compound shown in formula (I).

[0256] The following examples further illustrate the compounds, pharmaceutical compositions, and their applications provided by the present invention. In cases where the name and structure of the compounds described in this invention differ, the compound structure shall prevail. Example

[0257] Example 1: N-(4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-ylcyclopropaneformamide

[0258]

[0259] Step 1: Synthesis of 3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridine-2-amine

[0260] 4-Bromo-3-methoxypyridine-2-amine (1.0 g, 4.93 mmol), (2-methyl-2H-1,2,3-triazol-4-yl)boric acid (0.94 g, 7.39 mmol), potassium carbonate (1.70 g, 12.32 mmol), and Pd(dppf)Cl2 DCM (0.60 g, 0.74 mmol) were added to a reaction flask. Then, under nitrogen protection, 1,4-dioxane (30 mL) and water (5.0 mL) were added. Nitrogen was bubbled for 3 minutes, a condenser was attached, and the mixture was purged with nitrogen three times. The mixture was heated to 100 °C and stirred for 1 h. The mixture was then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 2) to give a pale yellow solid product (1.01 g, yield 99.93%). MS (ESI, pos.ion) m / z: 206.1 [M+H] + ;

[0261] 1 H NMR (600MHz, CDCl3) δ8.08 (s, 1H), 7.86 (d, J = 5.3Hz, 1H), 7.15 (d, J = 5.3Hz, 1H), 4.77 (s, 2H), 4.26 (s, 3H), 3.71 (s, 3H).

[0262] Step 2: Synthesis of ethyl 3-(4,6-dichloropyridin-3-yl)-3-oxopropionic acid

[0263] In the first reaction flask, 4,6-dichloronicotinic acid (10.0 g, 52.08 mmol), DCM (100 mL), and DMF (0.038 g, 0.52 mmol) were added sequentially. The system was cooled to 0 °C, and then oxaloyl chloride (7.93 g, 62.50 mmol) was slowly added dropwise. After the addition was complete, the temperature was raised to 40 °C and the mixture was stirred for 2 h. After the reaction was completed, the solvent was removed under reduced pressure to obtain a brown oily liquid, which was set aside for later use. In another reaction flask, potassium monoethyl malonate (10.64 g, 62.50 mmol) and acetonitrile (100 mL) were added. After the system was cooled to 0 °C, triethylamine (13.17 g, 130.2 mmol) and magnesium chloride (7.44 g, 78.12 mmol) were added. After the addition was complete, the mixture was stirred at this temperature for 2 h. The prepared acyl chloride (dissolved in 10 mL of DCM) from the first reaction flask was added dropwise to the second reaction system at 0 °C. After the addition was complete, the mixture was moved to room temperature and stirred overnight. Once the reaction was complete, the reaction system was cooled back to 0 °C, and the intermediate was decarboxylated by carefully adding HCl (60 mL, 2 M). The mixture was stirred in an ice bath for 1 hour, then transferred to a separatory funnel and extracted with EA (100 mL × 3). The combined organic layers were washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give a light brown solid product (9.65 g, yield 70.69%). MS (ESI, pos.ion) m / z: 262.1 [M+H] + .

[0264] Step 3: Synthesis of ethyl 2-(4,6-dichloronicotinyl)propionate-3,3-d3

[0265] Ethyl 3-(4,6-dichloropyridin-3-yl)-3-oxopropionate (3.68 g, 14.04 mmol) and acetonitrile (100 mL) were added to a reaction flask. After the system was cooled to 0 °C, potassium carbonate (2.33 g, 16.85 mmol) was added. After the addition was complete, the mixture was kept warm and stirred for 5 min. Then, deuterated iodomethane (10.18 g, 70.20 mmol) was added dropwise. After the addition was complete, the mixture was moved to room temperature and stirred for 2.0 h. The reaction was quenched with water (50 mL), and then extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 50 / 1) to give a light yellow oily liquid product (3.35 g, yield 85.48%).

[0266] MS(ESI,pos.ion)m / z:279.0[M+H]+ .

[0267] Step 4: Synthesis of 1-(6-chloro-4-hydroxypyridin-3-yl)prop-1-one 3,3,3-d3

[0268] Ethyl 2-(4,6-dichloronicotinyl)propionate-3,3-d3 (3.35 g, 12.00 mmol), acetic acid (20 mL), and concentrated hydrochloric acid (40 mL) were added to a reaction flask. After the addition was complete, the mixture was heated to 130 °C and stirred overnight. The mixture was then cooled to room temperature, diluted with water (60 mL), and extracted with ethyl acetate (60 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 50 / 1) to give an off-white solid product (1.28 g, yield 56.54%).

[0269] MS(ESI,pos.ion)m / z:189.1[M+H] + .

[0270] Step 5: Synthesis of 1-(4,6-dichloropyridin-3-yl)prop-1-one 3,3,3-d3

[0271] 1-(6-chloro-4-hydroxypyridin-3-yl)prop-1-one 3,3,3-d3 (2.74 g, 14.53 mmol) and acetonitrile (60 mL) were added to a reaction flask, followed by phosphorus oxychloride (44.56 g, 290.60 mmol). After the addition was complete, the mixture was heated to 85 °C and stirred for 1 h. The system was concentrated to remove phosphorus oxychloride and organic solvent. The residue was placed at 0 °C, and crushed ice was added. After the crushed ice dissolved, solid sodium carbonate was added to adjust the pH to approximately 7-8. Ethyl acetate (40 mL × 2) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 50 / 1) to give an off-white solid product (2.43 g, yield 80.79%).

[0272] MS(ESI,pos.ion)m / z:207.1[M+H] + ;

[0273] 1 H NMR (400MHz, CDCl3) δ8.53(s,1H),7.44(s,1H),2.95(s,2H).

[0274] Step 6: Synthesis of N-(4-chloro-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide

[0275] In a reaction flask, 1-(4,6-dichloropyridin-3-yl)prop-1-one 3,3,3-d3 (1.6 g, 7.73 mmol), cyclopropylamide (0.53 g, 6.18 mmol), Pd2(dba)3 (0.71 g, 0.77 mmol), XantPhos (0.89 g, 1.55 mmol), cesium carbonate (5.04 g, 15.46 mmol), and 1,4-dioxane (100 mL) were added sequentially. After the addition was complete, the mixture was purged with nitrogen three times, heated to 80 °C, and stirred for 1.5 h. The mixture was then evaporated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give a pale yellow solid product (1.22 g, yield 61.74%).

[0276] MS(ESI,pos.ion)m / z:256.1[M+H] + ;

[0277] 1 H NMR (600MHz, CDCl3) δ8.50(s,1H),8.47(s,1H),8.35(s,1H),2.97(s,2H),1.60–1.55(m,1H),1.16–1.11(m,2H),0.97–0.93(m,2H).

[0278] Step 7: Synthesis of N-(4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-ylcyclopropaneformamide)

[0279] 3-Methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridine-2-amine (75.0 mg, 0.37 mmol), N-(4-chloro-5-(propionyl-3,3,3-d3)pyridine-2-yl)cyclopropanecarboxamide (189.23 mg, 0.74 mmol), Pd2(dba)3 (34 mg, 0.037 mmol), XantPhos (43 mg, 0.074 mmol), cesium carbonate (240 mg, 0.74 mmol), and 1,4-dioxane (15 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was purged with nitrogen three times, heated to 108 °C, and stirred overnight. The system was then evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to give a pale yellow solid product (95 mg, yield 61.24%). MS(ESI,pos.ion)m / z:425.2[M+H] + ;

[0280] 1H NMR (600MHz, CDCl3) δ12.39(s,1H),9.82(s,1H),8.81(s,1H),8.41(s,1H),8.27(d,J=5.2Hz,1H),8.19(s,1H),7.4 5(d,J=5.2Hz,1H),4.28(s,3H),3.85(s,3H),3.04(s,2H),1.63–1.56(m,1H),1.20–1.16(m,2H),0.93–0.89(m,2H).

[0281] Example 2: N-(4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropaneformamide

[0282]

[0283] Step 1: Synthesis of 2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline

[0284] 3-Bromo-2-methoxyaniline (1.50 g, 7.42 mmol), (2-methyl-2H-1,2,3-triazol-4-yl)boric acid (1.88 g, 14.84 mmol), potassium carbonate (2.56 g, 18.55 mmol), and Pd(dppf)Cl2 DCM (0.91 g, 1.11 mmol) were added to a reaction flask under nitrogen protection. Then, 1,4-dioxane (80 mL) and water (12 mL) were added, and the mixture was bubbled with nitrogen for 3 minutes. A condenser was attached, and the mixture was purged with nitrogen three times. The mixture was heated to 100 °C and stirred for 12 h. The mixture was then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 200 / 1) to give a pale yellow solid product (1.45 g, yield 95.63%). MS (ESI, pos.ion) m / z: 205.2 [M+H] + ;

[0285] 1 H NMR (400MHz, CDCl3) δ8.02(s,1H),7.26–7.23(m,1H),6.99(t,J=7.8Hz,1H),6.75(dd,J=7.8,1.5Hz,1H),4.24(s,3H),3.90(s,2H),3.67(s,3H).

[0286] Step 2: Synthesis of 1-(6-chloro-4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)pyridin-3-yl)prop-1-one 3,3,3-d3

[0287] 2-Methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (200.0 mg, 0.97 mmol), 1-(4,6-dichloropyridin-3-yl)prop-1-one 3,3,3-d3 (200.0 mg, 0.97 mmol), and tetrahydrofuran (20 mL) were added to a reaction flask. The system was cooled to 0 °C, and then bis(trimethylsilylaminolithium) (3.88 mL, 3.88 mmol, 1 M) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 h. The reaction was quenched by adding saturated ammonium chloride solution (20 mL). The mixture was separated, and the organic phase was dried by rotary evaporation. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a pale yellow solid product (205.35 g, yield 56.72%). MS (ESI, pos.ion) m / z: 375.2 [M+H] + ;

[0288] 1 H NMR (600MHz, CDCl3) δ10.99(s,1H),8.78(s,1H),8.07(s,1H),7.83(dd,J=7.8,1.6Hz,1H),7.34( dd,J=7.9,1.5Hz,1H),7.25(t,J=7.9Hz,1H),6.97(s,1H),4.27(s,3H),3.68(s,3H),3.06(s,2H).

[0289] Step 3: Synthesis of N-(4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide

[0290] In a reaction flask, 1-(6-chloro-4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)pyridin-3-yl)prop-1-one 3,3,3-d3 (205 mg, 0.55 mmol), cyclopropylamide (70 mg, 0.83 mmol), Pd2(dba)3 (50 mg, 0.055 mmol), XantPhos (64 mg, 0.11 mmol), cesium carbonate (360 mg, 1.1 mmol), and 1,4-dioxane (50.0 mL) were added sequentially. After the addition was complete, the mixture was purged with nitrogen three times, heated to 105 °C, and stirred overnight. The mixture was then evaporated to dryness under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 100 / 1) to give a pale yellow solid product (144 mg, yield 62.18%). MS(ESI,pos.ion)m / z:424.2[M+H]+ ;

[0291] 1 H NMR (600MHz, CDCl3) δ11.23(s,1H),8.73(s,1H),8.51(s,1H),8.10(s,1H),8.07(s,1H),7.71(dd,J=7.9,1.4Hz,1H),7.51(dd,J=7.9,1.2Hz, 1H),7.25(t,J=7.9Hz,1H),4.25(s,3H),3.68(s,3H),3.01(s,2H),1.54(ddd,J=12.3,8.0,4.5Hz,1H),1.10–1.05(m,2H),0.89–0.85(m,2H).

[0292] Example 3 6-((4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)amino)pyridinenitrile

[0293]

[0294]

[0295] Step 1: Synthesis of 6-((4-chloro-5-(propionyl-3,3,3-d3)pyridin-2-yl)amino)pyridine nitrile

[0296] In a reaction flask, 1-(4,6-dichloropyridin-3-yl)propane-1-one-3,3,3-d3 (211.2 mg, 1.02 mmol), 2-amino-6-cyanopyridine (120.0 mg, 1.02 mmol), Pd2(dba)3 (93.4 mg, 0.10 mmol), XantPhos (118.0 mg, 0.20 mmol), cesium carbonate (664.7 mg, 2.04 mmol), and 1,4-dioxane (10.0 mL) were added sequentially. After the addition was complete, the mixture was purged with nitrogen three times, heated to 80 °C, and stirred for 3.0 h. The mixture was then evaporated to dryness under reduced pressure. The residue was subjected to column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give a pale yellow solid product (162.0 mg, yield 55.05%). MS (ESI, pos.ion) m / z: 290.2 [M+H] + ;

[0297] Step 2: Synthesis of 6-((4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)amino)pyridinenitrile

[0298] In a reaction flask, 3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (100.0 mg, 0.49 mmol), 6-((4-chloro-5-(propionyl-3,3,3-d3)pyridin-2-yl)amino)pyridine nitrile (142.0 mg, 0.49 mmol), Pd2(dba)3 (44.9 mg, 0.049 mmol), and Xantpho S (56.7 mg, 0.098 mmol), cesium carbonate (319.3 mg, 0.98 mmol), and 1,4-dioxane (10.0 mL) were added. After the addition was complete, the mixture was purged with nitrogen three times, sealed, and heated to 130 °C with stirring overnight. The system was then evaporated to dryness under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to give a light yellow solid product (155.0 mg, yield 69.38%).

[0299] MS(ESI,pos.ion)m / z:459.3[M+H] + ;

[0300] 1 H NMR(599MHz,DMSO-d6)δ12.45(s,1H),10.51(s,1H),9.76(s,1H),8.95(s,1H),8.35(d,J=3.2Hz,1H),8.32(s,1H),7 .97–7.86(m,1H),7.79(d,J=7.4Hz,1H),7.58(d,J=6.2Hz,1H),7.46(s,1H),4.28(s,3H),3.83(s,3H),3.13(s,2H).

[0301] Example 4: N-(4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)-3-methylbutyl-2-enamide

[0302]

[0303] Step 1: Synthesis of N-(4-chloro-5-(propionyl-3,3,3-d3)pyridin-2-yl)-3-methylbutyl-2-enamide

[0304] 1-(4,6-dichloropyridin-3-yl)propane-1-one-3,3,3-d3 (100.0 mg, 0.48 mmol), 3-methylbutyl-2-enamide (38.1 mg, 0.38 mmol), Pd2(dba)3 (44.0 mg, 0.048 mmol), XantPhos (56.0 mg, 0.096 mmol), cesium carbonate (310.0 mg, 0.96 mmol), and 1,4-dioxane (10.0 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was purged with nitrogen three times, heated to 80 °C, and stirred for 1.5 h. The mixture was then evaporated to dryness under reduced pressure. The residue was subjected to column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give a pale yellow solid product (96.0 mg, yield 73.70%). MS (ESI, pos.ion) m / z: 270.2 [M+H] + ;

[0305] 1 H NMR (600MHz, CDCl3) δ8.52(s,1H),8.47(s,1H),8.01(s,1H),5.75(dt,J=2.6,1.3Hz,1H),3.00(s,2H),2.28(d,J=1.1Hz,3H),1.98(d,J=1.1Hz,3H).

[0306] Step 2: Synthesis of N-(4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)-3-methylbutyl-2-enamide

[0307] In a reaction flask, 3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (50.0 mg, 0.24 mmol), N-(4-chloro-5-(propionyl-3,3,3-d3)pyridin-2-yl)-3-methylbutyl-2-enamide (90.0 mg, 0.33 mmol), Pd2(dba)3 (22.0 mg, 0.024 mmol), and Xan were added sequentially. tphos (27.8 mg, 0.048 mmol), cesium carbonate (156.4 mg, 0.48 mmol), and 1,4-dioxane (8.0 mL) were added. After the addition was complete, the mixture was purged with nitrogen three times, heated to 105 °C, and stirred overnight. The system was then evaporated to dryness under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to give a pale yellow solid product (45.0 mg, yield 42.12%). MS (ESI, pos.ion) m / z: 439.3 [M+H] + ; 1H NMR (600MHz, DMSO-d6) δ12.32(s,1H),10.46(s,1H),9.72(s,1H),8.95(s,1H),8.32(s,1H),8.19(d,J=5.2H z,1H),7.48(d,J=5.2Hz,1H),6.10(s,1H),4.28(s,3H),3.82(s,3H),3.14(s,2H),2.19(s,3H),1.88(s,3H).

[0308] Example 5: 1-(6-(6-fluoro-5-(2-hydroxypropane-2-yl)pyridin-2-yl)amino)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)pyridin-3-yl)prop-1-one-3,3,3-d3

[0309]

[0310] Step 1: Synthesis of 5-bromo-6-fluoropyridine-2-amine

[0311] 2-Amino-6-fluoropyridine (1.00 g, 8.92 mmol) and acetonitrile (20.0 mL) were added to a reaction flask and the mixture was cooled to 0 °C. NBS (1.67 g, 9.37 mmol) was dissolved in acetonitrile (5.0 mL) and slowly added dropwise to the reaction system. After the addition was complete, the mixture was allowed to rise to room temperature. Once the reaction was complete, water (20.0 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed with saturated brine (10 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give a white solid product (1.70 g, yield 99.78%). MS (ESI, pos.ion) m / z: 191.1 [M+H] + .

[0312] Step 2: Synthesis of 2-(6-amino-2-fluoropyridin-3-yl)prop-2-ol

[0313] 5-Bromo-6-fluoropyridine-2-amine (1.70 g, 8.90 mmol) and tetrahydrofuran (50.0 mL) were added to a reaction flask under nitrogen protection and the temperature was lowered to -78 °C. Butyllithium (12.46 mL, 31.15 mmol, 2.5 M in hexane) was added dropwise, and the mixture was stirred for 5 min. Acetone (5.17 g, 89.0 mmol) was dissolved in tetrahydrofuran (5.0 mL) and added dropwise to the reaction system. After the addition was complete, the mixture was allowed to rise to room temperature and react for 2 h. After the reaction was complete, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give a brown oily product (0.50 g, yield 33.01%).

[0314] MS(ESI,pos.ion)m / z:171.2[M+H] + ;

[0315] 1 H NMR (600MHz, CDCl3) δ7.73 (dd, J=10.5, 8.2Hz, 1H), 6.34 (dd, J=8.1, 1.6Hz, 1H), 4.46 (s, 2H), 3.75 (s, 1H), 1.61 (s, 6H).

[0316] Step 3: Synthesis of 1-(4-chloro-6-(6-fluoro-5-(2-hydroxypropane-2-yl)pyridin-2-yl)amino)pyridin-3-yl)prop-1-one-3,3,3-d3

[0317] 2-(6-amino-2-fluoropyridin-3-yl)prop-2-ol (99.0 mg, 0.58 mmol), 1-(4,6-dichloropyridin-3-yl)prop-1-one-3,3,3-d3 (120.0 mg, 0.58 mmol), Pd2(dba)3 (53.0 mg, 0.058 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (67.0 mg, 0.12 mmol), cesium carbonate (380.0 mg, 1.16 mmol), and 1,4-dioxane (10.0 mL) were added to a reaction flask under nitrogen protection and the mixture was heated to 80 °C. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1) to give a brown oily product (142.0 mg, yield 71.90%). MS(ESI,pos.ion)m / z:341.1[M+H] + ;

[0318] Step 4: Synthesis of 1-(6-(6-fluoro-5-(2-hydroxypropane-2-yl)pyridin-2-yl)amino)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)pyridin-3-yl)prop-1-one-3,3,3-d3

[0319] Add 1-(4-chloro-6-(6-fluoro-5-(2-hydroxypropane-2-yl)pyridin-2-yl)amino)pyridin-3-yl)prop-1-one-3,3,3-d3 (70.0 mg, 0.21 mmol), 3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (34.0 mg, 0.17 mmol), and Xphos-Pd-G2 (17.0 mg, 0.021 mmol) to the sealing tube. The reaction mixture was prepared by adding 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (24.0 mg, 0.042 mmol), cesium carbonate (140.0 mg, 0.42 mmol), and 1,4-dioxane (10.0 mL) under nitrogen protection and heating to 150 °C. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 120 / 1) to give a white solid product (19.5 mg, yield 18.63%).

[0320] MS(ESI,pos.ion)m / z:510.2[M+H] + ;

[0321] 1 H NMR (600MHz, CDCl3) δ12.47(s,1H),9.49(s,1H),8.89(s,1H),8.26(d,J=4.4Hz,1H),8.24(s,1H),8. 02–7.96(m,1H),7.86(s,1H),7.53–7.45(m,2H),4.32(s,3H),3.91(s,3H),3.07(s,2H),1.69(s,6H).

[0322] Example 6: 1-(6-((5-fluoropyridin-2-yl)amino)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)pyridin-3-yl)propane-1-one-3,3,3-d3

[0323]

[0324] Step 1: Synthesis of 1-(4-chloro-6-((5-fluoropyridin-2-yl)amino)pyridin-3-yl)propane-1-one-3,3,3-d3

[0325] 1-(4,6-dichloropyridin-3-yl)propane-1-one-3,3,3-d3 (130.5 mg, 0.63 mmol), 2-amino-5-fluoropyridine (70.0 mg, 0.63 mmol), Pd2(dba)3 (57.7 mg, 0.063 mmol), XantPhos (72.9 mg, 0.13 mmol), cesium carbonate (410.5 mg, 1.26 mmol), and 1,4-dioxane (8.0 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was purged with nitrogen three times, heated to 80 °C, and stirred for 4.0 h. The mixture was then evaporated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give a yellow solid product (82.0 mg, yield 46.04%). MS (ESI, pos.ion) m / z: 283.1 [M+H] + ;

[0326] Step 2: Synthesis of 1-(6-((5-fluoropyridin-2-yl)amino)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)pyridin-3-yl)propane-1-one-3,3,3-d3

[0327] In a reaction flask, 3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (65.0 mg, 0.32 mmol), 1-(4-chloro-6-((5-fluoropyridin-2-yl)amino)pyridin-3-yl)propane-1-one-3,3,3-d3 (81.4 mg, 0.29 mmol), Pd2(dba)3 (29.3 mg, 0.032 mmol), and 1,1'-di( Dicyclohexylphosphine-ferrocene (37.0 mg, 0.064 mmol), cesium carbonate (208.5 mg, 0.64 mmol), and 1,4-dioxane (8.0 mL) were added. After the addition was complete, the mixture was purged with nitrogen three times, sealed, and heated to 150 °C with stirring overnight. The system was then evaporated to dryness under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to give a yellow solid product (52.0 mg, yield 39.71%).

[0328] MS(ESI,pos.ion)m / z:452.3[M+H] + ;

[0329] 1H NMR(600MHz,DMSO-d6)δ12.34(s,1H),10.19(s,1H),9.38(s,1H),8.93(s,1H),8.59–8.0 5(m,3H),7.81(s,1H),7.71(s,1H),7.46(s,1H),4.29(s,3H),3.83(s,3H),3.11(s,2H).

[0330] Example 7: 6-(cyclopropaneformamide)-4-((4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methoxypyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0331]

[0332]

[0333] Step 1: Synthesis of N-(4-bromo-3-methoxypyridin-2-yl)-N-[(tert-butyl)carbonyl] tert-butyl carbamate

[0334] 2-Amino-4-bromo-3-methoxypyridine (5.0 g, 24.63 mmol) and acetonitrile (50.0 mL) were added to a reaction flask and the temperature was lowered to 0 °C. Di-tert-butyl dicarbonate (16.13 g, 73.89 mmol) and 4-dimethylaminopyridine (0.60 g, 4.93 mmol) were dissolved in dichloromethane (50.0 mL) and added dropwise to the reaction system. After the addition was complete, the temperature was increased to room temperature. Once the reaction was complete, water (50 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (30 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (v / v) = 100 / 1) to give a white solid product (9.90 g, yield 99.69%). MS (ESI, pos.ion) m / z: 403.2 [M+H] + ;

[0335] Step 2: Synthesis of N-[(tert-butoxy)carbonyl]-N-(3-methoxy-4-(4H,5H,6H-pyrrolo[1,2-b]pyrazol-2-yl)pyridin-2-yl)carbamate tert-butyl ester

[0336] In a reaction flask, N-(4-bromo-3-methoxypyridin-2-yl)-N-[(tert-butyl)carbonyl]carbamate tert-butyl ester (8.50 g, 21.08 mmol), pinacol diboronate (10.71 g, 42.16 mmol), Pd(dppf)Cl2 DCM (1.72 g, 2.11 mmol), potassium acetate (6.21 g, 63.24 mmol), and 1,4-dioxane (200.0 mL) were added. Under nitrogen protection, the mixture was heated to 105 °C and reacted for 5 h. After the reaction was complete, 2-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (2.37 g, 12.65 mmol), potassium carbonate (5.83 g, 42.16 mmol), and Pd(dppf)Cl2 were added. DCM (0.86 g, 1.05 mmol) and water (10.0 mL) were reacted overnight at 105 °C under nitrogen protection. After the reaction was complete, water (20.0 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give a light brown oily product (4.00 g, yield 44.08%).

[0337] MS(ESI,pos.ion)m / z:431.2[M+H] + ;

[0338] 1 H NMR (600MHz, CDCl3) δ8.23(d,J=5.1Hz,1H),7.84(d,J=5.1Hz,1H),6.65(s,1H),4.24(t, J=7.3Hz,2H),3.75(s,3H),3.02–2.96(m,2H),2.72–2.62(m,2H),1.42(d,J=6.0Hz,18H).

[0339] Step 3: Synthesis of 4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methoxypyridine-2-amine

[0340] N-[(tert-butoxy)carbonyl]-N-(3-methoxy-4-(4H,5H,6H-pyrrolo[1,2-b]pyrazol-2-yl)pyridin-2-yl)tert-butyl carbamate (4.10 g, 9.52 mmol) and dichloromethane (100.0 mL) were added to a reaction flask, the temperature was lowered to 0 °C, and hydrogen chloride (59.5 mL, 238 mmol, 4 M in diox.) was added dropwise. The mixture was then brought to room temperature. After the reaction was complete, saturated sodium bicarbonate solution was added to adjust the pH to 7. The mixture was extracted with ethyl acetate (10 mL × 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (v / v) = 80 / 1) to give a blackish-green solid product (1.27 g, yield 57.91%).

[0341] MS(ESI,pos.ion)m / z:231.2[M+H] + ;

[0342] 1 H NMR(600MHz,DMSO-d6)δ7.64(d,J=5.3Hz,1H),6.98(d,J=5.3Hz,1H),6.55(s,1H), 5.85(s,2H),4.16–4.10(m,2H),3.60(s,3H),2.92–2.86(m,2H),2.59–2.53(m,2H).

[0343] Step 4: Synthesis of 6-chloro-4-((4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methoxypyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0344] Add 4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methoxypyridine-2-amine (200.0 mg, 0.87 mmol), 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (450.0 mg, 2.17 mmol), and tetrahydrofuran (20.0 mL) to a reaction flask, under nitrogen protection, and cool to 0 °C. Then add bis(trimethylsilylaminolithium) (3.48 mL, 3.48 mmol, 1 M) dropwise. The reaction was carried out at room temperature for 2 hours (in THF). After the reaction was completed, saturated ammonium chloride (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (v / v) = 80 / 1) to give a yellow solid product (270.0 mg, yield 77.17%). MS (ESI, pos.ion) m / z: 403.2 [M+H]+ ;

[0345] 1 H NMR (600MHz, CDCl3) δ12.41(s,1H),9.39(s,1H),8.37(s,1H),8.13(d,J=5.2Hz,1H),7.56(d,J=5.2 Hz,1H),6.72(s,1H),4.26(t,J=7.3Hz,2H),3.88(s,3H),3.01(t,J=7.3Hz,2H),2.74–2.63(m,2H).

[0346] Step 5: Synthesis of 6-(cyclopropanecarboxamide)-4-((4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methoxypyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0347] Add 6-chloro-4-((4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methoxypyridin-2-yl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (270.0 mg, 0.67 mmol), cyclopropionamide (230.0 mg, 2.68 mmol), tris(dibenzylacetone)dipalladium (61.0 mg, 0.067 mmol), 4,5 -Diphenylphosphine-9,9-dimethyloxanthracene (78.0 mg, 0.13 mmol), cesium carbonate (440.0 mg, 1.34 mmol), and 1,4-dioxane (20.0 mL) were reacted under nitrogen protection at 130 °C. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (v / v) = 80 / 1) to give a white solid product (163.0 mg, yield 53.87%).

[0348] MS(ESI,pos.ion)m / z:452.3[M+H] + ;

[0349] 1H NMR (600MHz, CDCl3) δ12.31(s,1H),10.06(s,1H),8.57(s,1H),8.27(s,1H),8.21(d,J=5.3Hz,1H),7.51(d,J=5.3Hz,1H),6.72(s,1H),4.2 5(t,J=7.3Hz,2H),3.86(s,3H),3.05–2.95(m,2H),2.74–2.61(m,2H),2.04(dd,J=12.8,7.0Hz,1H),1.25–1.21(m,2H),1.00–0.96(m,2H).

[0350] Example 8: N-(4-((4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-3-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropaneformamide

[0351]

[0352] Step 1: Synthesis of 4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)pyridine-3-amine

[0353] 5-Bromo-4-methoxypyridine-3-amine (1.50 g, 7.39 mmol), (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (1.88 g, 14.78 mmol), potassium carbonate (2.55 g, 18.47 mmol), and Pd(dppf)Cl2 DCM (0.91 g, 1.11 mmol) were added to a reaction flask. Then, under nitrogen protection, 1,4-dioxane (80.0 mL) and water (12.0 mL) were added. Nitrogen was bubbled for 3 minutes, a condenser was attached, and nitrogen was purged three times. The mixture was heated to 100 °C and stirred overnight. The mixture was then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to give a pale yellow solid product (1.0 g, yield 65.96%). MS(ESI,pos.ion)m / z:206.2[M+H] + ;

[0354] 1 H NMR (400MHz, CDCl3) δ8.45(s,1H),8.09(s,1H),7.97(s,1H),4.26(s,3H),3.90(s,2H),3.72(s,3H).

[0355] Step 2: Synthesis of 1-(6-chloro-4-((4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-3-yl)amino)pyridin-3-ylprop-1-one-3,3,3-d3

[0356] 4-Methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)pyridine-3-amine (200.0 mg, 0.97 mmol), 1-(4,6-dichloropyridin-3-yl)prop-1-one-3,3,3-d3 (200.0 mg, 0.97 mmol), and tetrahydrofuran (20.0 mL) were added to a reaction flask. The system was cooled to 0 °C, and then bis(trimethylsilylaminolithium) (3.88 mL, 3.88 mmol, 1 M) was added dropwise. After the addition was complete, the mixture was moved to room temperature and stirred for 2 h. The reaction was quenched by adding saturated ammonium chloride solution (20.0 mL). The mixture was separated, and the organic phase was dried by rotary evaporation. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to give an off-white solid product (223.0 mg, yield 61.43%). MS(ESI,pos.ion)m / z:376.2[M+H] + ;

[0357] 1 H NMR (599MHz, CDCl3) δ10.88(s,1H),9.03(s,1H),8.81(s,1H),8.52(s,1H),8.02(s,1H),6.78(s,1H),4.29(s,3H),3.81(s,3H),3.07(s,2H).

[0358] Step 3: Synthesis of N-(4-((4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-3-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropaneformamide

[0359] In a reaction flask, 1-(6-chloro-4-((4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-3-yl)amino)pyridin-3-ylprop-1-one-3,3,3-d3 (220 mg, 0.59 mmol), cyclopropionamide (75.0 mg, 0.89 mmol), Pd2(dba)3 (54 mg, 0.059 mmol), and XantPhos (68.0 mg, 0.059 mmol) were added sequentially. 12 mmol of dichloromethane (12 mmol), cesium carbonate (380.0 mg, 1.18 mmol), and 1,4-dioxane (50.0 mL) were added. After the addition was complete, the mixture was purged with nitrogen three times, heated to 105 °C, and stirred overnight. The system was then evaporated to dryness under reduced pressure. The residue was subjected to column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to give a pale yellow solid product (150 mg, yield 60.37%). MS (ESI, pos.ion) m / z: 425.2 [M+H] + ;

[0360] 1 H NMR (599MHz, CDCl3) δ10.98(s,1H),8.94(s,1H),8.74(s,1H),8.62(s,1H),8.47(d,J=4.3Hz,1H),8.02(s,1H) ,7.88(s,1H),4.27(s,3H),3.79(s,3H),3.03(s,2H),1.55–1.49(m,1H),1.07–1.02(m,2H),0.88–0.83(m,2H).

[0361] Biological experiments

[0362] The LC / MS / MS system used for analysis included an Agilent 1200 series vacuum degassing furnace, a binary injection pump, an autosampler for well plates, a column oven, and an Agilent G6430 triplex quadrupole mass spectrometer with an electrospray ionization (ESI) source. Quantitative analysis was performed in MRM mode, and the MRM conversion parameters are shown in Table A.

[0363] Table A

[0364] Multiple reaction detection scanning 490.2→383.1 Fragmentation voltage 230V Capillary voltage 55V Dry gas temperature 350℃ atomizer 0.28MPa Dryer flow rate 10L / min

[0365] Analysis was performed using an Agilent XDB-C18 2.1 × 30 mm, 3.5 μM column, with 5 μL of sample injected. Analytical conditions: the mobile phase consisted of 0.1% formic acid aqueous solution (A) and 0.1% formic acid methanol solution (B). The flow rate was 0.4 mL / min. The mobile phase gradient is shown in Table B.

[0366] Table B

[0367] time gradient of mobile phase B 0.5min 5％ 1.0min 95％ 2.2min 95％ 2.3min 5％ 5.0min termination

[0368] In addition, an Agilent 6330 series LC / MS / MS spectrometer was used for analysis, equipped with a G1312A binary syringe pump, a G1367A autosampler, and a G1314C UV detector; the LC / MS / MS spectrometer used an ESI radiation source. For optimal analysis, each analyte underwent appropriate cation modeling and MRM conversion using standard solutions. A Capcell MP-C18 column (100 x 4.6 mm ID, 5 μM, Phenomenex, Torrance, California, USA) was used during analysis. The mobile phase was 5 mM ammonium acetate, 0.1% methanol aqueous solution (A): 5 mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70 / 30, v / v); the flow rate was 0.6 mL / min; the column temperature was maintained at room temperature; and 20 μL of sample was injected.

[0369] Example A: Stability of the compounds of the present invention in human and mouse liver microsomes

[0370] The stability of the compounds of this invention in human and mouse liver microsomes can be tested using the following two methods:

[0371] Method 1:

[0372] Human or mouse liver microsomes were placed in polypropylene tubes for double-well incubation. A typical incubation mixture consisted of human or mouse liver microsomes (0.5 mg protein / mL), the target compound (5 μM), and 200 μL of NADPH (1.0 mM) potassium phosphate buffer (PBS, 100 mM, pH 7.4). The compound was dissolved in DMSO and diluted with PBS to a final DMSO concentration of 0.05%. The mixture was incubated in a water bath at 37°C with air circulation. After a 3-minute pre-incubation, the protein was added to the mixture to initiate the reaction. The reaction was terminated at different time points (0, 5, 10, 15, 30, and 60 min) by adding an equal volume of ice-cold acetonitrile. Samples were stored at –80°C until LC / MS / MS analysis.

[0373] The linear concentration range of each target compound was determined, and then the concentration of the target compound in human or mouse liver microsomal incubation mixture was determined by LC / MS / MS.

[0374] Denatured microsomes were used as a negative control, and dextromethorphan (70 μM) as a positive control in parallel incubation experiments. The negative control was incubated at 37°C, with the reaction terminated at different time points (0, 15, and 60 minutes); the positive control was incubated at 37°C, with the reaction terminated at different time points (0, 5, 10, 15, 30, and 60 minutes). Positive and negative control samples were used in each assay to ensure the integrity of the microsome incubation system.

[0375] Method 2:

[0376] Furthermore, the stability data of the compounds described in this invention in human or mouse liver microsomes can also be obtained through the following experiments:

[0377] Human or mouse liver microsomes were placed in double-well polypropylene tubes for incubation. A typical incubation mixture consisted of human or mouse liver microsomes (final concentration: 0.5 mg protein / mL), the target compound (final concentration: 1.5 μM), and 30 μL of K-buffer solution (containing 1.0 mM EDTA, 100 mM, pH 7.4). The compound was dissolved in DMSO and diluted with K-buffer solution to a final concentration of 0.2%. After a 10-minute pre-incubation, 15 μL of NADPH (final concentration: 2 mM) was added to initiate the enzymatic reaction. The entire experiment was performed in incubation tubes at 37°C. The reaction was terminated at different time points (0, 15, 30, and 60 minutes) by adding 135 μL of acetonitrile (containing IS). The mixture was centrifuged at 4,000 rpm for 10 minutes to remove the protein, and the supernatant was collected for analysis by LC-MS / MS.

[0378] In the above experiments, ketoselin (1 μM) was selected as a positive control and incubated at 37°C. The reaction was terminated at different time points (0, 15, 30, and 60 minutes). A positive control sample was included in each assay to ensure the integrity of the microsomal incubation system.

[0379] Data Analysis

[0380] For each reaction, the concentration (expressed as a percentage) of the compound during incubation in human or mouse liver microsomes was plotted as a percentage of the zero time point to infer the intrinsic hepatic clearance CL in vivo. int(ref.:Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y. Prediction of humanhepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. Drug Metabolism and Disposition 2001, 29: 1316-1324.).

[0381] The results showed that the compound of the present invention has good stability in human and mouse liver microparticles.

[0382] Example B: Pharmacokinetics of the compounds of the present invention in mice, rats, dogs, and monkeys after intravenous injection and oral administration. Learning Evaluation

[0383] This invention evaluated the pharmacokinetic studies of the compounds of this invention in mice, rats, dogs, or monkeys. The compounds of this invention were administered in aqueous solution or in an aqueous solution of 2% HPMC + 1% Tween-80, 5% DMSO + 5% saline solution, 4% MC, or capsules. For intravenous administration, animals were given doses of about 0.5, 0.6, 1, or 2 mg / kg. For oral doses (po), the doses were 5 or 10 mg / kg for rats and mice, and 10 mg / kg for dogs and monkeys. Blood samples (0.3 mL) were collected at time points of 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12, and 24 hours and centrifuged at 3,000 or 4,000 rpm for 10 minutes. Plasma solutions were collected and stored at -20°C or -70°C until the LC / MS / MS analysis described above was performed. The results showed that when the compounds provided by the present invention were administered intravenously or orally, the compounds exhibited good pharmacokinetic properties, including good absorption and good oral bioavailability.

[0384] The results showed that the compound described in this invention exhibited excellent pharmacokinetic properties, including good absorption (AUC). last Good oral bioavailability (F).

[0385] Example C: JAK2 / TYK2 Cell Level Viability Assay

[0386] TYK2 belongs to the JAK family and can accept ligands to act on signal-regulated downstream signal transduction activation proteins (STATs) via phosphorylation. STAT phosphorylation can regulate the expression of downstream related genes, leading to changes in physiological functions such as cell proliferation and differentiation. IL-12 mediates IFNγ expression in NK92 cells through JAK2 / TYK2.

[0387] Therefore, inhibiting TYK2 activity can suppress the decrease in IFNγ expression caused by this cascade pathway. Since IL-2 can induce NK92 proliferation and IFNγ production through receptor-coupled JAK1 / 3, the influence of IL-2 needs to be excluded. This experiment evaluated the activity of compounds on JAK2 / TYK2 by detecting IFNγ expression at various compound concentrations.

[0388] The test compound was dissolved in DMSO to prepare a 20 mM stock solution, which was stored at -20°C for later use. The stock solution was then diluted 10-fold with DMSO to a 2 mM solution, and then diluted with culture medium to the initial concentration of 10. 5 nM, then diluted 3 times with medium containing 5% DMSO to obtain a concentration gradient of 10. 5 nM, 33333.3nM, 11111.1nM, 3703.70nM, 1234.57nM, 411.523nM, 137.174nM, 45.7247nM, 15.2416nM; 10 μl of the above drug concentrations was added to a 96-well plate to obtain a final concentration of 10 4 nM, 3333.3nM, 1111.1nM, 370.4nM, 123.5nM, 41.1nM, 13.7nM, 4.6nM, 1.52nM.

[0389] NK92 cells were resuscitated and cultured. Sixteen hours before the experiment, the medium was changed to interleukin-free medium. Cells were resuspended in IL-12-containing medium after centrifugation and seeded in 96-well plates at a density of 20,000 cells / well. 10 μl of the above-mentioned gradually diluted medium was added and incubated for 24 h. The supernatant was collected by centrifugation, diluted 3-fold with pure water, and the IFNγ concentration in the supernatant was detected by ELISA to calculate the IC50. 50 Values. See Table 1 for the results.

[0390] Table 1. Experimental results of the activity of the compounds provided in the embodiments of the present invention against JAK2 / TYK2 cells.

[0391]

[0392] The experimental results show that the compound described in this invention has good inhibitory activity at the JAK2 / TYK2 cell level.

[0393] Example D: Analysis of the rat BBB experiment

[0394] Experimental animals: Six SD rats were administered the drug via gavage and divided into two groups (1 h and 5 h) according to the sampling time, with 3 rats per time point. The rats were fasted overnight before administration. Dosage and administration: The dosage was 5 mg / kg, and the administration volume was 10 ml / kg. The test compound was administered via gavage according to the animal's body weight.

[0395] Sample collection: Animals were anesthetized at 1 h and 5 h after drug administration, and whole blood was collected. Plasma was prepared by centrifugation with EDTA-K2 anticoagulation. After euthanasia of rats, cerebrospinal fluid and brain tissue were collected. Brain tissue was homogenized with a certain proportion of homogenizing medium. Plasma, cerebrospinal fluid and brain tissue homogenate were stored at low temperature for analysis.

[0396] Sample pretreatment and analysis: Collected plasma samples were treated using an organic reagent precipitation method. The supernatant was then analyzed for sample concentration using LC-MS / MS. Data processing: Based on the obtained plasma, cerebrospinal fluid, and brain tissue concentration data at each time point, the blood-brain barrier (T / P) ratio was calculated. A higher ratio indicates stronger blood-brain barrier penetration, and vice versa.

[0397] Table 4. Experimental results of the blood-brain barrier penetration ability of the compounds provided in the embodiments of the present invention.

[0398]

[0399] The comparative compound A is Example 36 of patent application WO2022241171A1, and its structure is as follows:

[0400] The experimental results show that the compound described in this invention has a strong ability to penetrate the blood-brain barrier.

[0401] Finally, it should be noted that there are other ways to implement this invention. Accordingly, the embodiments of this invention are described as examples, but are not limited to the content described in this invention. It is understood that the above embodiments are exemplary and should not be construed as limiting the invention. Those skilled in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of this invention. These may also be modifications made within the scope of this invention or equivalent content added to the claims. All publications or patents cited in this invention are to be used as references in this invention.

Claims

1. A compound, which is a compound of formula (I), or a stereoisomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof of a compound of formula (I), in: E is either N or CH; X is N or CR x ; Y is N or CR y ; Z is N or CR z ; R x R y and R z Each of the following can be independently H, D, F, Cl, Br, I, -OH, -NH2, -NO2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 1-6 Alkylamino; R 2 For H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl or heterocyclic group consisting of 3-10 atoms; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The cycloalkyl group and the heterocyclic group consisting of 3-10 atoms are each independently and optionally surrounded by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; R 3 For H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Deuterated alkyl groups; R 1 For -OR a -C(O)R a -C(O)OR a -NR a R b -NR c C(O)R d -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b -NR a S(O)2R b -C(O)NR a S(O)2R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-12 atoms; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 atoms are each independently and optionally surrounded by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substituted by haloalkoxy groups, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2; Each R a R b R c and R d H, D, C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-12 atoms, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 atoms are each independently and optionally surrounded by 1, 2, 3 or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 It is substituted by cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, and substituents such as -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2.

2. The compound according to claim 1, wherein... R 2 For H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl or heterocyclic group consisting of 3-8 atoms; wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl group and the heterocyclic group consisting of 3-8 atoms are each independently and optionally surrounded by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; R 3 For H, D, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Deuterated alkyl groups.

3. The compound according to claim 1 or 2, wherein... R 2 The following are not directly related to the preceding text: H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CD3, CH2CD3, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ... The tert-butyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolyl, imidazoalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl groups are each independently and optionally substituted by 1, 2, 3, 4, or 5 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy groups; R 3 It can be H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, CD3 or CH2CD3.

4. The compound according to any one of claims 1-3, wherein R 1 For -OR a -C(O)R a -C(O)OR a -NR a R b -NR c C(O)R d -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b -NR a S(O)2R b -C(O)NR a S(O)2R b C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-10 atoms; wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally surrounded by 1, 2, 3, 4 or 5 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Substituted by haloalkoxy groups, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2; Each R a R b R c and R d H, D, C independently 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-10 atoms, wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally surrounded by 1, 2, 3 or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkyl, C 3-6 It is substituted by cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, and substituents such as -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2.

5. The compound according to any one of claims 1-4, wherein... R 1 is -OR a 、-C(O)R a 、-C(O)OR a 、-NR a R b 、-NR c C(O)R d 、-NR a C(O)OR b 、-C(O)NR a R b 、-S(O)2R a 、-S(O)2NR a R b 、-NR a S(O)2R b 、-C(O)NR a S(O)2R b Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetyl, aziroxy, pyrroleyl Imidazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, azacyclobutyl, pyrrolyl, imidazoalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are each independently and optionally composed of 1, 2, 3, 4, or 5 groups selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, methyl, ethyl, n-propyl Substituents of -methyl, -isopropyl, -n-butyl, -isobutyl, -sec-butyl, -tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2; Each R a R b R c and R d Independently, H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-methylpropenyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, 4,5-dihydrooxazolyl, 5,6-dihydro-4H-pyrrolo[1,2-B]pyrazolyl, phenyl, naphthyl, pyrrolidinyl, pyrazolyl, imidazole, triazolyl Azolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-methylpropenyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, 4,5-dihydrooxazolyl, 5,6-dihydrooxazolyl 4H-pyrrolo[1,2-B]pyrazolyl, phenyl, naphthyl, pyrrolithyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl are each independently and optionally separated by 1, 2, 3, or 4 of the following groups: D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH It is substituted by substituents such as 2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, -CH2OH, -CH2CH2OH, -C(CH3)2OH, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2.

6. The compound according to any one of claims 1-5, wherein... R x R y and R z Each of the following can be independently H, D, F, Cl, Br, I, -OH, -NH2, -NO2, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or C 1-4 Alkylamino.

7. The compound according to any one of claims 1-6, wherein... R x R y and R z Each can be independently H, D, F, Cl, Br, I, -OH, -NH2, -NO2, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, -CH2NH2 or -CH2CH2NH2.

8. The compound according to any one of claims 1-7, wherein it is a compound of formula (Ia) or (Ib), or a stereoisomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the compound of formula (Ia) or (Ib). in, R 1 R 2 R 3 X, Y and Z each have the definition as described in any one of claims 1-7.

9. A compound having one of the following structures, or a stereoisomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof:

10. A pharmaceutical composition comprising the compound of any one of claims 1-9, further comprising at least one of pharmaceutically acceptable excipients, carriers, and solvents.

11. Use of the compound of any one of claims 1-9 or the pharmaceutical composition of claim 10 in the preparation of a medicament for the prevention, treatment, cure or relief of TYK2-mediated diseases; The diseases mediated by TYK2 are neurodegenerative diseases, autoimmune diseases, viral diseases, or proliferative diseases.

12. The use according to claim 11, wherein the TYK2-mediated disease is a neuroinflammatory condition, optic neuritis, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, Parkinson's disease, dementia, psoriasis, lupus erythematosus, inflammatory bowel disease, psoriatic arthritis, arthritis, vasculitis, fibrosis, dermatitis, skin aging, encephalitis, lupus nephritis, multiple sclerosis, ALS, myasthenia gravis, mental illness, schizophrenia, epilepsy, spinal cord injury, sleep disorder, brain injury, stroke, neuropsychiatric lupus, diabetic encephalopathy, sepsis-associated encephalopathy, central nervous system tumors, Huntington's disease, postoperative neurological syndrome, pain, itching, depression, narcolepsy, hydrocephalus, ankylosing spondylitis, respiratory disease, diabetes, inflammatory eye disease, hepatitis, cardiovascular disease, systemic sclerosis, organ transplantation, alopecia areata, acne, eczema, vitiligo, Sjögren's syndrome, viral inflammation, or cancer.

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