CN114075220A

CN114075220A - Substituted heteroaryl compounds, compositions and uses thereof

Info

Publication number: CN114075220A
Application number: CN202110910806.4A
Authority: CN
Inventors: 习宁; 王斌; 陈武宏; 陈鹏; 白长林; 许望津; 李敏雄; 陈疏影
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Sunshine Lake Pharma Co Ltd
Priority date: 2020-08-13
Filing date: 2021-08-10
Publication date: 2022-02-22

Abstract

The invention provides a substituted heteroaryl compound, a composition and application thereof. Wherein the compound is a compound shown in a formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound shown in the formula (I). The invention also provides pharmaceutical compositions comprising the compounds, which compounds and pharmaceutical compositions modulate the activity of JAK kinases, particularly TYK2, for the prevention, treatment and alleviation of diseases or disorders mediated by JAK kinase activity.

Description

Substituted heteroaryl compounds, compositions and uses thereof

Technical Field

The invention belongs to the field of medicaments, and particularly relates to novel substituted heteroaryl compounds serving as JAK kinase activity inhibitors, a preparation method thereof, a pharmaceutical composition containing the compounds, and application of the compounds and the pharmaceutical composition in treatment of various diseases. More specifically, the compounds of the present invention may act as inhibitors of the activity or function of tyrosine kinase 2(TYK 2).

Background

Janus kinases (JAKs) are intracellular non-receptor type tyrosine kinases that transduce cytokine mediated signals through the JAK-STAT pathway. The JAK family plays an important role in cytokine-dependent regulation of proliferation and cellular functions involved in immune responses. Cytokines bind to their receptors and cause receptor dimerization, which can promote the cross-phosphorylation of JAKs and also the phosphorylation of specific tyrosine motifs within cytokine receptors. STATs that recognize these phosphorylation motifs are aggregated on receptors and then activated during JAK-dependent tyrosine phosphorylation. Upon activation, STATs dissociate from receptors, dimerize, and translocate to the nucleus, bind to specific DNA sites, and alter transcription.

Currently, there are four known mammalian JAK family members: JAK1(Janus kinase-1), JAK2(Janus kinase-2), JAK3(Janus kinase, leukocytes, JAKL, L-JAK and Janus kinase-3) and TYK2 (protein tyrosine kinase 2). Different Janus kinase family members are responsible for signaling different cytokines and their receptors, JAK1, JAK2 and TYK2 are widely expressed, whereas JAK3 is reported to be preferentially expressed in Natural Killer (NK) cells, but not in other T cells.

TYK2 is associated with IFN- α (alpha interferon), IL-6 (interleukin-6), IL-10 (interleukin-10), IL-12 (interleukin-12) and IL-23 (interleukin-23) signaling. Biochemical studies and knockout mice have revealed an important role for TYK2 in immunity. TYK 2-deficient mice are able to grow and reproduce, but exhibit a variety of immunodeficiencies, mainly high sensitivity to infection and defects in tumor surveillance. Conversely, inhibition of TYK2 may improve the ability to fight allergic, autoimmune and inflammatory diseases. In particular, targeting TYK2 appears to be an innovative strategy for the treatment of IL-12, IL-23-or type I IFN-mediated diseases. Such diseases include, but are not limited to, rheumatoid arthritis, 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-.

The European Committee has recently approved the fully human monoclonal antibody Stelara (Ustekinumab) targeting the p40 subunit common to IL-12 and IL-23 cytokines for the treatment of moderate to severe plaque psoriasis (Krueger et al, 2007, N.Engl. J.Med.,356: 580-92; Reich et al, 2009, nat. Rev. drug Discov.,8: 355-. In addition, antibody ABT-874, targeting both the IL-12 and IL-23 pathways, was subjected to clinical trials for the treatment of Crohn's disease (Mannon et al, N.Engl. J.Med.,2004,351: 2069-79).

Since the IL-12 and IL-23 signaling pathways are mediated by phosphorylation of the Jak2/TYK2 heterodimer via STAT3/4, the development of inhibitors of Jak2 and Tyk2 is of high interest to the scientific and medical community. See, e.g., Liang et al, j.med.chem. [ journal of drug chemistry ] (2013)56: 4521-. However, blocking JAK2 activity is considered problematic because JAK2 also regulates the erythropoietin signaling pathway and its inhibition is associated with undesirable hematologic toxicities such as anemia, neutropenia, and thrombocytopenia. See, e.g., Liang et al, j.med.chem. [ journal of drug chemistry ] (2013)56: 4521-; albanduaali, Hematology Rebies [ Hematology review ] (2009)1: e1056-61.

Therefore, in view of the high degree of sequence homology between JAK family kinase members, the development of selective TYK2 inhibitors that avoid the inhibition of JAK2 and/or JAK1 is a significant challenge.

Disclosure of Invention

The present invention provides a class of compounds that inhibit, modulate and/or modulate the activity of JAK kinases for the treatment of inflammatory diseases, autoimmune diseases, inflammatory diseases, proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, and complications thereof. The invention also provides processes for preparing these compounds, methods of using these compounds to treat the above-mentioned disorders in mammals, especially humans, and pharmaceutical compositions containing these compounds. The compound and the composition thereof have better clinical application prospect. Compared with the existing similar compounds, the compound of the invention has better pharmacological activity, pharmacokinetic property, physicochemical property and/or lower toxicity. Specifically, the compound of the invention shows better inhibitory activity and optimized TYK2 selectivity on target TYK2, and shows good absorption and higher bioavailability in pharmacokinetic experiments in animals; the compound of the invention has no cardiotoxicity and good safety. Therefore, the compound of the present invention has more excellent drugability.

Specifically, the method comprises the following steps:

in one aspect, the invention relates to a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

wherein:

x is N or CR^a(ii) a Y is N or CR^b(ii) a Z is N or CR^c；

R¹is-NH₂、C_1-6Alkyl radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C_6-10Aryl or heteroaryl of 5 to 12 atoms, wherein the-NH group₂、C_1-6Alkyl radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C_6-10Aryl and 5-12 atoms consisting of heteroaryl can be independently optionally substituted by 1,2,3,4 or 5 atoms selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by the radical hydroxyalkoxy;

each R⁶And R⁷Independently H, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-O-, heterocyclic radical of 3-8 atoms, C_6-10Aryl or heteroaryl of 5-10 atoms, wherein-OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-O-, heterocyclic radical of 3-8 atoms, C_6-10Aryl and heteroaryl of 5 to 10 atoms may be independently optionally substituted by 1,2,3,4 or 5R^xRadical takeGeneration;

each V¹、V²、V³And V⁴Independently is- (CR)⁹R¹⁰)_n-、-(CR⁹R¹⁰)_n-O-、-(CR⁹R¹⁰)_n-S-、-(CR⁹R¹⁰)_n-NR¹¹-、-(CR⁹R¹⁰)_n-C(＝O)-、-(CR⁹R¹⁰)_n-O-C(＝O)-、-(CR⁹R¹⁰)_n-C(＝O)-O-、-(CR⁹R¹⁰)_n-S (═ O) -or- (CR)⁹R¹⁰)_n-S(＝O)₂-；

Each R⁹And R¹⁰Independently H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy or C_3-6Cycloalkyl, wherein said-OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy and C_3-6The cycloalkyl groups can be independently and optionally substituted by 1,2,3,4 or 5 groups selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted with a group of hydroxyalkoxy; or

R⁹、R¹⁰Together with the carbon atom to which they are attached form C_3-6Cycloalkyl or heterocyclyl consisting of 3 to 6 atoms, wherein said C is_3-6Cycloalkyl and heterocyclyl consisting of 3 to 6 atoms may be independently optionally substituted by 1,2,3,4 or 5 atoms selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Oxo (═ O), C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by a group of hydroxyalkoxy;

R¹¹is H, D, C_1-6Alkyl radical, C_1-6Haloalkyl or C_3-6Cycloalkyl, wherein said C_1-6Alkyl radical、C_1-6Haloalkyl and C_3-6The cycloalkyl groups can be independently and optionally substituted by 1,2,3,4 or 5 groups selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Oxo (═ O), C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_1-3Hydroxyalkoxy and C_3-6Cycloalkyl groups are substituted by the radicals;

each R^a、R^bAnd R^cIndependently H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-8Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C_6-10Aryl or heteroaryl of 5-12 atoms, wherein-OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-8Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C_6-10Aryl and 5-12 atoms consisting of heteroaryl can be independently optionally substituted by 1,2,3,4 or 5 atoms selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by the radical hydroxyalkoxy;

each R^xIndependently F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy or C_3-6Cycloalkyl, wherein said-OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy and C_3-6The cycloalkyl groups can be independently and optionally substituted by 1,2,3,4 or 5 groups selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by the radical hydroxyalkoxy;

each n is independently 0,1 or 2.

In some embodiments, R¹is-NH₂、C_1-4Alkyl radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms, wherein the-NH group₂、C_1-4Alkyl radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl and 5-10 atoms consisting of heteroaryl can be independently optionally substituted by 1,2,3,4 or 5 atoms selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In some embodiments, R¹is-NH₂Methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, N-ethylpropyl-2-amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the group-NH-is a substituent selected from the group consisting of a carboxyl group, a salt₂Methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino, N-ethylpropyl-2-amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl groups may be independently selectedOptionally 1,2,3,4 or 5 substituents selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, each R is⁶And R⁷Independently H, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-O-, heterocyclic radical of 3-6 atoms, C_6-10Aryl or heteroaryl of 5-10 atoms, wherein-OH, -NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-O-, heterocyclic radical of 3-6 atoms, C_6-10Aryl and heteroaryl of 5 to 10 atoms may be independently optionally substituted by 1,2,3,4 or 5R^xSubstituted by a group; wherein each R^xHaving the definitions as described in the present invention.

In some embodiments, each R is⁶And R⁷Independently H, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, alkynePropyl, 1-propynyl, 1-alkynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-O-, cyclobutyl-O-, cyclopentyl-O-, cyclohexyl-O-, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein, the-OH and-NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-alkynbutyl, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-O-, cyclobutyl-O-, cyclopentyl-O-, cyclohexyl-O-, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, and the like, Thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl may be independently optionally substituted with 1,2,3,4 or 5R^xSubstituted by a group; wherein each R^xHaving the definitions as described in the present invention.

In some embodiments of the present invention, the substrate is,each R⁹And R¹⁰Independently H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein-OH, -NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl may independently optionally be substituted by 1,2,3,4 or 5 substituents selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH is substituted by a group; or

R⁹、R¹⁰And the carbon atom to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl groups are each independently unsubstituted or substituted with 1,2,3,4 or 5 substituents independently selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Oxo (═ O), methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH is substituted by a group;

R¹¹h, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are each independently unsubstituted or substituted by 1,2,3,4 or 5 substituents independently selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Oxo (═ O), methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH、-OCH₂CH₂OH, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In some embodiments of the present invention, the substrate is,

is composed of

Wherein each R¹¹Having the definitions as described in the present invention.

In some embodiments, each R is^a、R^bAnd R^cIndependently H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5-10 atoms, wherein-OH, -NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl and 5-10 atoms consisting of heteroaryl can be independently optionally substituted by 1,2,3,4 or 5 atoms selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In some embodiments, each R is^a、R^bAnd R^cIndependently H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-alkynbutyl, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein, the-OH and-NH are shown.₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-alkynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxyAryl, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl may be independently optionally substituted with 1,2,3,4 or 5 substituents selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, each R is^xIndependently F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy or C_3-6Cycloalkyl, wherein said-OH, -NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy and C_3-6The cycloalkyl groups can be independently and optionally substituted by 1,2,3,4 or 5 groups selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In some embodiments, each R is^xIndependently F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-propargyl, 2-propargyl, 3-propargyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein-OH, -NH, -OH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-propargyl, 2-propargyl, 3-propargyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups may independently optionally be substituted by 1,2,3,4 or 5 substituents selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) of the present invention, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of pharmaceutically acceptable excipients, carriers, vehicles.

In other embodiments, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent selected from at least one of corticosteroids, rolipram, caftarine, cytokine inhibitory anti-inflammatory drugs, interleukin-10, glucocorticoids, salicylates, nuclear translocation inhibitors, steroid antivirals, antiproliferatives, antimalarials, TNF-a inhibitors.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament for the prevention, treatment, or amelioration of a TYK2 mediated disease.

In some embodiments, the TYK 2-mediated disease described herein is an inflammatory disease, an autoimmune disease, a metabolic disease, a destructive bone disease, a proliferative disease, an angiogenic disorder, sepsis, septic shock, shigellasis, a neurodegenerative disease, or retinitis.

In other embodiments, the TYK 2-mediated disease of the invention is pancreatitis, asthma, allergy, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, discoid lupus erythematosus, scleroderma, chronic thyroiditis, grave's disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory responses, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, neeld syndrome, gout, rheumatoid arthritis, psoriasis, rheumatoid arthritis, Traumatic arthritis, rheumatoid arthritis, acute synovitis, pancreatic beta cell disease, a disease characterized by massive neutrophil infiltration, rheumatoid spondylitis, gouty arthritis, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, allograft rejection, fever due to infection, myalgia due to infection, cachexia secondary to infection, keloid formation, scar tissue formation, fever, influenza, osteoporosis, osteoarthritis, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, Shigella disease, Alzheimer's disease, Parkinson's disease, cerebral ischemia or neurodegenerative disease due to traumatic injury, angiogenic disorders, viral diseases, inflammatory bowel disease, CMV retinitis, AIDS, ARC, herpes, stroke, myocardial ischemia, ischemia in stroke heart attack, organ hypoxia, vascular proliferation, cardiac reperfusion injury, renal reperfusion injury, thrombosis, cardiac hypertrophy, coagulation-induced enzymatic platelet aggregation, endotoxemia, toxic shock syndrome, prostaglandin endoperoxidase synthase-2-associated disease state, or pemphigus vulgaris.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the preparation of a medicament for the activity of a JAK kinase.

In some embodiments, the JAK kinase of the invention is TYK2 kinase.

In yet another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (I).

Biological test results show that the compound provided by the invention can be used as a better JAK kinase inhibitor, especially as a TYK2 kinase inhibitor.

Any of the embodiments of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any of the embodiments of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict each other.

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be followed unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 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.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.

"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow the general definitions 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.

Many organic compounds exist in an optically active form, i.e., they have 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 denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain 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.

Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates 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 in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

Racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods by methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)^nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,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)。

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure that may be substituted is replaced with a particular substituent. Unless otherwise indicated, a substituted group may have one substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.

The terms "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the scenario where the heterocyclic group is substituted with an alkyl and the scenario where the heterocyclic group is not substituted with an alkyl.

The term "unsubstituted" means that the specified group bears no substituents.

The term "optionally substituted with … …" is used interchangeably with the term "unsubstituted or substituted with … …", i.e., the structure is unsubstituted or substituted with one or more substituents described herein.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… … independently" and "… … independently" and "… … independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C₁-C₆Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 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 other embodiments, the alkyl group contains 1 to 6 carbon atoms; in other embodiments, the alkyl group contains 2 to 6 carbon atoms; in still other embodiments, the alkyl group contains 1 to 4 carbon atoms; in still other embodiments, the alkyl group contains 1 to 3 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl group (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl group (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) Tert-butyl (t-Bu, -C (CH)₃)₃) N-pentyl (-CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 2, 2-dimethylpropyl (neopentyl, -CH)₂C(CH₃)₂CH₃) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) N-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃) N-heptyl, n-octyl, and the like.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp²A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In some embodiments, alkenyl groups contain 2 to 8 carbon atoms; in other embodiments, alkenyl groups contain 2 to 6 carbon atoms; in still other embodiments, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)₂) Propenyl (-CH ═ CHCH)₃) Allyl (-CH)₂CH＝CH₂) And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In some embodiments, alkynyl groups contain 2-8 carbon atoms; in other embodiments, alkynyl groups contain 2-6 carbon atoms; in still other embodiments, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)₂C.ident.CH), 1-propynyl (-C.ident.C-CH)₃) 1-alkynylbutyl (-CH)₂CH₂C ≡ CH), 2-alkynylbutyl (-CH)₂C≡CCH₃) 3-alkynylbutyl (-C≡CCH₂CH₃) And so on.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In some embodiments, alkoxy groups contain 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in still other embodiments, alkoxy groups contain 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) 1-pentyloxy (n-pentyloxy, -OCH)₂CH₂CH₂CH₂CH₃) 2-pentyloxy (-OCH (CH)₃)CH₂CH₂CH₃) 3-pentyloxy (-OCH (CH))₂CH₃)₂) 2-methyl-2-butoxy (-OC (CH))₃)₂CH₂CH₃) 3-methyl-2-butoxy (-OCH (CH)₃)CH(CH₃)₂) 3-methyl-l-butoxy (-OCH)₂CH₂CH(CH₃)₂) 2-methyl-l-butoxy (-OCH)₂CH(CH₃)CH₂CH₃) And so on.

The terms "hydroxyalkyl" and "hydroxyalkoxy" mean alkyl or alkoxy, as the case may be, substituted with one or more hydroxy groups, wherein "hydroxyalkyl" is substituted with one or more hydroxy groups"hydroxyalkyl" may be used interchangeably, and examples include, but are not limited to, hydroxymethyl (-CH)₂OH), hydroxyethyl (-CH)₂CH₂OH,-CHOHCH₃) Hydroxypropyl group (-CH)₂CH₂CH₂OH,-CH₂CHOHCH_3,-CHOHCH₂CH_3,) Hydroxy methoxy (-OCH)₂OH), and the like.

The term "haloalkoxy" denotes an alkoxy group substituted by one or more halogen atoms, wherein alkoxy has the meaning described herein; examples include, but are not limited to, trifluoromethoxy (-OCF)₃) And the like.

The term "haloalkyl" denotes an alkyl group substituted with one or more halogen atoms, wherein alkyl has the meaning described herein. In some of these embodiments, the haloalkyl group contains 1 to 12 carbon atoms; in still other embodiments, the haloalkyl group contains 1 to 10 carbon atoms; in still other embodiments, the haloalkyl group contains 1 to 8 carbon atoms; in still other embodiments, the haloalkyl group contains 1 to 6 carbon atoms; in other embodiments, the haloalkyl group contains 1 to 4 carbon atoms, and in other embodiments, the haloalkyl group contains 1 to 3 carbon atoms. Examples include, but are not limited to, difluoromethyl, trifluoromethyl, trifluoroethyl, and the like.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. In some embodiments, cycloalkyl groups contain 3 to 12 carbon atoms; in other embodiments, cycloalkyl groups contain 3 to 8 carbon atoms; in other embodiments, cycloalkyl groups contain 4 to 7 carbon atoms; in other embodiments, the cycloalkyl group contains 3 to 6 carbon atoms. In some embodiments, cycloalkyl is C comprising 7 to 12 carbon atoms_7-12Cycloalkyl, which further comprises C_7-12Spirobicycloalkyl radical, C_7-12Fused bicycloalkyl and C_7-12Bridged bicycloalkyl; in other embodiments, cycloalkyl is C containing 8 to 11 carbon atoms_8-11Cycloalkyl, which further comprises C_8-11Spirobicycloalkyl radical, C₈-₁₁Fused bicycloalkyl and C_8-11Bridged bicyclic alkyl. In some embodiments, C_3-6Cycloalkyl specifically refers to a ring containing 3 to 6 carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a mono-, bi-or tricyclic ring system containing 3 to 12 ring atoms, which is monovalent or multivalent, saturated or partially unsaturated, and non-aromatic, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Heterocyclyl includes saturated heterocyclyl (i.e., heterocycloalkyl) and partially unsaturated heterocyclyl. In some embodiments, heterocyclyl is a heterocyclyl consisting of 3-8 atoms; in other embodiments, heterocyclyl is a heterocyclyl consisting of 3-6 atoms.

Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl, oxazepinyl, thiazalinyl, thiazepinyl, thia-piperazinyl, homopiperidinyl, oxazepanyl, and the like

Radicals (e.g. 1, 4-oxaza)

1, 2-oxaza

Alkyl), diazepine

Radicals (e.g. 1, 4-diazepine)

1, 2-diazepines

Basic), dioxa

Radicals (e.g. 1, 4-dioxa)

1, 2-dioxan

Basic), a sulfur aza

Radicals (e.g. 1, 4-thiazepine)

1, 2-thiaza radical

Indolyl), indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxolyl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, 2-azaspiro [4.4]Nonanyl, 1, 6-dioxaspiro [4.4 ]]Nonanyl, 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, octahydrocyclopenta [ c]Pyrrolyl, hexahydrofuro [3,2-b ] groups]Furyl and dodecahydroisoquinolinyl, and the like. In heterocyclic radicals of-CH₂Examples of-radicals substituted by-C (═ O) -include, but are not limited to, 1, 1-dioxoisothiazolinone-2-yl, pyrrolidin-2-on-1-yl, pyrrolidin-1-yl, and pyrrolidin-b,Imidazolidin-2-one-1-yl, oxazolidin-2-one-3-yl, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl and 3, 5-dioxopiperidinyl. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane, 1-dioxothiomorpholinyl, 1-dioxotetrahydrothienyl, and 1, 1-dioxotetrahydro-2H-thiopyranyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.

The term "s-atom composed", where s is an integer, typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is s. For example, piperidinyl is a heterocycloalkyl group of 6 atoms, and 1,2,3, 4-tetrahydronaphthyl is a carbocyclyl group of 10 atoms.

The term "unsaturated" as used herein means that the group contains one or more unsaturations.

The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).

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

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms in the ring and one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include phenyl, naphthyl and anthracenyl. The aryl group may independently be optionally substituted with one or more substituents described herein.

The term "heteroaryl" denotes aromatic, containing monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, and at least one ring system containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound".

Examples of heteroaryl groups include, but are in no way limited to: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), indazolyl (e.g., 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyridyl, pyrazolo [4,3-c ] pyridyl, pyrazolo [3,4-b ] pyridyl, pyrazolo [1,5-a ] pyrimidyl, pyrazolyl, and the like, 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 ] pyridinyl, purinyl, furyl (e.g. 2-furyl, pyridazinyl [1,2,4] triazolo [1,5-a ] pyridinyl, purinyl, furyl, 3-furyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridonyl, pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrimidonyl, pyrimidinedione, pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl, 3-pyrazinyl), Thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl), pyrazolonyl, isothiazolyl, oxadiazolyl (e.g., 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl), 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl, and the like.

The terms "alkylamino" and "alkylamino" are used interchangeably and include "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. Wherein, in some embodiments, the alkylamino group is one or two C_1-12The alkyl group is attached to a nitrogen atom to form a lower alkylamino group. In other embodiments, alkylamino is one or two C_1-6The alkyl group is attached to a nitrogen atom to form a lower alkylamino group. In other embodiments, alkylamino is one or two C_1-4The alkyl group is attached to a nitrogen atom to form a lower alkylamino group. In still other embodiments, the alkylamino group is one or two C_1-3The alkyl group is attached to a nitrogen atom to form a lower alkylamino group. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and examples of alkylamino include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, N-ethylpropyl-2-amino, and the like.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)₁-C₂₄) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: t.higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium 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 S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formic acidSalts, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, embonate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N⁺(C₁-C₄Alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present 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 of solvent molecules that is water.

The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

As used herein, "inflammatory disease" refers to any disease, disorder or condition of excessive inflammatory symptoms, host tissue damage or loss of tissue function due to excessive or uncontrolled inflammatory response. "inflammatory disease" also refers to a pathological condition mediated by leukocyte influx and/or neutrophil chemotaxis.

As used herein, "inflammation" refers to a local protective response caused by tissue damage or destruction that serves to destroy, dilute, or separate (sequester) harmful substances from damaged tissue. Inflammation is significantly linked to leukocyte influx and/or neutrophil chemotaxis. Inflammation can result from infection by pathogenic organisms and viruses, as well as from non-infectious means, such as trauma or reperfusion following myocardial infarction or stroke, immune and autoimmune responses to foreign antigens. Thus, inflammatory diseases that may be treated with the disclosed compounds include: diseases associated with specific defense system reactions as well as non-specific defense system reactions.

By "specific defense system" is meant that components of the immune system respond to the presence of a particular antigen. Examples of inflammation arising from specific defense system responses include classical responses to foreign antigens, autoimmune diseases, and delayed hypersensitivity responses (mediated by T-cells). Chronic inflammatory diseases, rejection of transplanted solid tissues and organs (such as rejection of kidney and bone marrow transplants), and Graft Versus Host Disease (GVHD) are other examples of specific defense systems against inflammatory reactions.

As used herein, "autoimmune disease" refers to any collection of diseases of tissue damage associated with humoral or cell-mediated responses to the body's own components.

As used herein, "allergy" refers to any symptom of developing an allergy, tissue damage, or loss of tissue function. As used herein, "arthritic disease" refers to any disease characterized by inflammatory injury to the joints attributable to various etiologies. As used herein, "dermatitis" refers to any of a large family of skin diseases characterized by skin inflammation attributable to various etiologies. As used herein, "transplant rejection" refers to any immune response against a transplanted tissue, such as an organ or cell (e.g., bone marrow), characterized by loss of function of the transplanted or surrounding tissue, pain, swelling, leukocytosis, and thrombocytopenia. The therapeutic methods of the invention include methods for treating diseases associated with inflammatory cell activation.

The terms "cancer" and "cancerous" refer to or describe the physiological condition in a patient that is often characterized by uncontrolled cell growth. A "tumor" comprises one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma (carcinoma), lymphoma, blastoma, sarcoma, and leukemia, or lymphoproliferative disorder (lymphoproliferative disorders). More specific examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer (including small-cell lung cancer, non-small cell lung cancer (NSCLC), adenocarcinoma of the lung and squamous carcinoma of the lung), cancer of the peritoneum, hepatocellular cancer, gastric or gastric cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, testicular tumor, bladder cancer, hepatoma (hepatoma), breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer (kidney or renal cancer), prostate cancer, vulval cancer, thyroid cancer, medullary thyroid cancer, melanoma, retinoblastoma, liver cancer (hepatoma), anal cancer, penile carcinoma, acute myelogenous leukemia, acute lymphocytic leukemia, Chronic Myelogenous Leukemia (CML), Chronic lymphocytic leukemia and head and neck cancer.

Description of the Compounds of the invention

The invention discloses a novel compound which can be used as an inhibitor of JAK kinase activity. Compounds which are inhibitors of JAK protein kinases are useful in the treatment of diseases associated with JAK kinase activity, in particular diseases associated with TYK2 activity, such diseases including inflammatory diseases, autoimmune diseases, metabolic diseases, destructive bone diseases, proliferative diseases, angiogenic disorders, sepsis, septic shock, shigellasis, neurodegenerative diseases or retinitis.

In one aspect, the invention relates to a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

wherein each X, Y, Z, R¹、R⁶、R⁷、V¹、V²、V³And V⁴All have the meaning described herein.

In some embodiments, X is N or CR^a(ii) a Wherein R is^aHave the meaning as described in the present invention.

In some embodiments, Y is N or CR^b(ii) a Wherein R is^bHave the meaning as described in the present invention.

In some embodiments, Z is N or CR^c(ii) a Wherein R is^cHave the meaning as described in the present invention.

In some embodiments, R¹is-NH₂、C_1-6Alkyl radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C_6-10Aryl or heteroaryl of 5 to 12 atoms, wherein the-NH group₂、C_1-6Alkyl radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C_6-10Aryl and 5-12 atoms consisting of heteroaryl can be independently optionally substituted by 1,2,3,4 or 5 atoms selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R¹is-NH₂、C_1-4Alkyl radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms, wherein the-NH group₂、C_1-4Alkyl radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl and 5-10 atoms consisting of heteroaryl can be independently optionally substituted by 1,2,3,4 or 5 atoms selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R¹is-NH₂Methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, N-ethylpropyl-2-amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the group-NH-is a substituent selected from the group consisting of a carboxyl group, a salt₂Methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino, N-ethylpropyl-2-amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl may independently optionally be substituted with 1,2,3,4 or 5 substituents selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy、-OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R⁶Is H, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-O-, heterocyclic radical of 3-8 atoms, C_6-10Aryl or heteroaryl of 5-10 atoms, wherein-OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-O-, heterocyclic radical of 3-8 atoms, C_6-10Aryl and heteroaryl of 5 to 10 atoms may be independently optionally substituted by 1,2,3,4 or 5R^xSubstituted by a group; wherein R is^xHave the meaning as described in the invention

In other embodiments, R⁶Is H, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-O-, heterocyclic radical of 3-6 atoms, C_6-10Aryl or heteroaryl of 5-10 atoms, wherein-OH, -NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-O-, heterocyclic radical of 3-6 atoms, C_6-10Aryl and heteroaryl of 5 to 10 atoms may be independently optionally substituted by 1,2,3,4 or 5R^xSubstituted by a group; wherein R is^xHave the meaning as described in the present invention.

In other embodiments, R⁶Is H, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl、CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-alkynbutyl, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-O-, cyclobutyl-O-, cyclopentyl-O-, cyclohexyl-O-, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, and the like, Thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein said-OH, -NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-alkynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, and the like,Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-O-, cyclobutyl-O-, cyclopentyl-O-, cyclohexyl-O-, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl may independently optionally be substituted with 1,2,3,4 or 5R^xSubstituted by a group; wherein R is^xHave the meaning as described in the present invention.

In some embodiments, R⁷Is H, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-O-, heterocyclic radical of 3-8 atoms, C_6-10Aryl or heteroaryl of 5-10 atoms, wherein-OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-O-, heterocyclic radical of 3-8 atoms, C_6-10Aryl and heteroaryl of 5 to 10 atoms may be independently optionally substituted by 1,2,3,4 or 5R^xSubstituted by a group; wherein R is^xHave the meaning as described in the invention

In other embodiments, R⁷Is H, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-O-, heterocyclic radical of 3-6 atoms, C_6-10Aryl or heteroaryl of 5-10 atoms, wherein-OH, -NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-O-, group of 3-6 atomsTo a heterocyclic group, C_6-10Aryl and heteroaryl of 5 to 10 atoms may be independently optionally substituted by 1,2,3,4 or 5R^xSubstituted by a group; wherein R is^xHave the meaning as described in the present invention.

In other embodiments, R⁷Is H, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-alkynbutyl, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-O-, cyclobutyl-O-, cyclopentyl-O-, cyclohexyl-O-, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, and the like, Thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein said-OH, -NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-alkynbutyl, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-O-, cyclobutyl-O-, cyclopentyl-O-, cyclohexyl-O-, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, and the like, Thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl may be independently optionally substituted with 1,2,3,4 or 5R^xSubstituted by a group; wherein R is^xHave the meaning as described in the present invention.

In some embodiments, V¹Is- (CR)⁹R¹⁰)_n-、-(CR⁹R¹⁰)_n-O-、-(CR⁹R¹⁰)_n-S-、-(CR⁹R¹⁰)_n-NR¹¹-、-(CR⁹R¹⁰)_n-C(＝O)-、-(CR⁹R¹⁰)_n-O-C(＝O)-、-(CR⁹R¹⁰)_n-C(＝O)-O-、-(CR⁹R¹⁰)_n-S (═ O) -or- (CR)⁹R¹⁰)_n-S(＝O)₂-; wherein R is⁹、R¹⁰、R¹¹And n has the meaning described in the present invention.

In other embodiments, V¹is-CH₂-, -O-or-CH₂-O-。

In some embodiments, V²Is- (CR)⁹R¹⁰)_n-、-(CR⁹R¹⁰)_n-O-、-(CR⁹R¹⁰)_n-S-、-(CR⁹R¹⁰)_n-NR¹¹-、-(CR⁹R¹⁰)_n-C(＝O)-、-(CR⁹R¹⁰)_n-O-C(＝O)-、-(CR⁹R¹⁰)_n-C(＝O)-O-、-(CR⁹R¹⁰)_n-S (═ O) -or- (CR)⁹R¹⁰)_n-S(＝O)₂-; wherein R is⁹、R¹⁰、R¹¹And n has the meaning described in the present invention.

In other embodiments, V²is-CH₂-, -O-or-CH₂-O-。

In some embodiments, V³Is- (CR)⁹R¹⁰)_n-、-(CR⁹R¹⁰)_n-O-、-(CR⁹R¹⁰)_n-S-、-(CR⁹R¹⁰)_n-NR¹¹-、-(CR⁹R¹⁰)_n-C(＝O)-、-(CR⁹R¹⁰)_n-O-C(＝O)-、-(CR⁹R¹⁰)_n-C(＝O)-O-、-(CR⁹R¹⁰)_n-S (═ O) -or- (CR)⁹R¹⁰)_n-S(＝O)₂-; wherein R is⁹、R¹⁰、R¹¹And n has the meaning described in the present invention.

In other embodiments, V³is-CH₂-、-O-、-CH₂-O-、-C(＝O)-O-、-NHCH₃-or-CH₂-NHCH₃-。

In some embodiments, V₄Is- (CR)⁹R¹⁰)_n-、-(CR⁹R¹⁰)_n-O-、-(CR⁹R¹⁰)_n-S-、-(CR⁹R¹⁰)_n-NR¹¹-、-(CR⁹R¹⁰)_n-C(＝O)-、-(CR⁹R¹⁰)_n-O-C(＝O)-、-(CR⁹R¹⁰)_n-C(＝O)-O-、-(CR⁹R¹⁰)_n-S (═ O) -or- (CR)⁹R¹⁰)_n-S(＝O)₂-; wherein R is⁹、R¹⁰、R¹¹And n has the meaning described in the present invention.

In other embodiments, V⁴is-CH₂-、-O-、-CH₂-O-、-C(＝O)-O-、-NHCH₃-or-CH₂-NHCH₃-。

In some embodiments, R⁹Is H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy or C_3-6Cycloalkyl, wherein said-OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy and C_3-6The cycloalkyl groups can be independently and optionally substituted by 1,2,3,4 or 5 groups selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3A group substituted with a group of hydroxyalkoxy groups.

In other embodiments, R⁹Is H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein-OH, -NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl may independently optionally be substituted by 1,2,3,4 or 5 substituents selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R¹⁰Is H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy or C_3-6Cycloalkyl, wherein said-OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy and C_3-6The cycloalkyl groups can be independently and optionally substituted by 1,2,3,4 or 5 groups selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3A group substituted with a group of hydroxyalkoxy groups.

In other embodiments, R¹⁰Is H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein-OH, -NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl may independently optionally be substituted by 1,2,3,4 or 5 substituents selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R⁹、R¹⁰Together with the carbon atom to which they are attached form C_3-6Cycloalkyl or heterocyclyl consisting of 3 to 6 atoms, wherein said C is_3-6Cycloalkyl and heterocyclyl consisting of 3 to 6 atoms may be independently optionally substituted by 1,2,3,4 or 5 atoms selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Oxo (═ O), C_1-3Alkyl radical、C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The substituted group of the hydroxyl alkoxy is substituted.

In other embodiments, R⁹、R¹⁰And the carbon atom to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl groups are each independently unsubstituted or substituted with 1,2,3,4 or 5 substituents independently selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Oxo (═ O), methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R¹¹Is H, D, C_1-6Alkyl radical, C_1-6Haloalkyl or C_3-6Cycloalkyl, wherein said C_1-6Alkyl radical, C_1-6Haloalkyl and C_3-6The cycloalkyl groups can be independently and optionally substituted by 1,2,3,4 or 5 groups selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Oxo (═ O), C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_1-3Hydroxyalkoxy and C_3-6Cycloalkyl groups are substituted.

In other embodiments, R¹¹H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are each independently unsubstituted or substituted by 1,2,3,4 or 5 substituents independently selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Oxo (═ O), methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH、-OCH₂CH₂OH, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In some embodiments of the present invention, the substrate is,

is composed of

Wherein R is¹¹Have the meaning described in the present invention.

In some embodiments, R^aIs H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-8Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C_6-10Aryl or heteroaryl of 5-12 atoms, wherein-OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-8Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C_6-10Aryl and 5-12 atoms consisting of heteroaryl can be independently optionally substituted by 1,2,3,4 or 5 atoms selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^aIs H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5-10 atoms, wherein-OH, -NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl and 5-10 atoms consisting of heteroaryl can be independently optionally substituted by 1,2,3,4 or 5 atoms selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^aIs H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butylRadical, tert-butyl radical, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-alkynbutyl, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein, the-OH and-NH are shown.₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-propargyl, 2-propargyl, 3-propargyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, and the likePentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl may independently optionally be substituted with 1,2,3,4 or 5 substituents selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R^bIs H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-8Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C_6-10Aryl or heteroaryl of 5-12 atoms, wherein-OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-8Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C_6-10Aryl and 5-12 atoms consisting of heteroaryl can be independently optionally substituted by 1,2,3,4 or 5 atoms selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^bIs H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5-10 atoms, wherein-OH, -NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl and 5-10 atoms consisting of heteroaryl can be independently optionally substituted by 1,2,3,4 or 5 atoms selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^bIs H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-alkynbutyl, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein, the-OH and-NH are shown.₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-alkynbutyl, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl may independently optionally be substituted with 1,2,3,4, or 5 substituents selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R^cIs H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-8Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C_6-10Aryl or heteroaryl of 5-12 atoms, wherein-OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-8Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C_6-10Aryl and 5-12The heteroaryl group consisting of atoms may be independently optionally substituted by 1,2,3,4 or 5 atoms selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^cIs H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5-10 atoms, wherein-OH, -NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl and 5-10 atoms consisting of heteroaryl can be independently optionally substituted by 1,2,3,4 or 5 atoms selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^cIs H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Ethylene, ethyleneA phenyl group, a propenyl group, an allyl group, an ethynyl group, a propargyl group, a 1-propynyl group, a 1-alkynylbutyl group, a 2-alkynylbutyl group, a methoxy group, an ethoxy group, a 1-propoxy group, a 2-propoxy group, a 1-butoxy group, a 2-methyl-l-propoxy group, a 2-butoxy group, a 2-methyl-2-propoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an oxetanyl group, an azetidinyl group, a pyrrolidinyl group, a tetrahydrofuranyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a phenyl group, a naphthyl group, a benzimidazolyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, a furyl group, a thienyl group, a thiazolyl group, an oxazolyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group or a pyridazinyl group, wherein, the-OH and-NH are shown.₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-alkynbutyl, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl may independently optionally be substituted with 1,2,3,4, or 5 substituents selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethylOxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R^xIs F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy or C_3-6Cycloalkyl, wherein said-OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy and C_3-6The cycloalkyl groups can be independently and optionally substituted by 1,2,3,4 or 5 groups selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^xIs F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy or C_3-6Cycloalkyl, wherein said-OH, -NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy and C_3-6The cycloalkyl groups can be independently and optionally substituted by 1,2,3,4 or 5 groups selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^xIs F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-propargyl, 2-propargyl, 3-propargyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein-OH, -NH, -OH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-propargyl, 2-propargyl, 3-propargyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups may independently optionally be substituted by 1,2,3,4 or 5 substituents selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, n is 0,1, or 2.

In another aspect, the present invention relates to a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a solvate, a hydrate, a metabolite, an ester, a pharmaceutically acceptable salt, or a prodrug thereof, of a compound of one of the following, but is in no way limited to:

unless otherwise specified, stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts of the compounds of formula (I) or prodrugs thereof are included within the scope of the present invention.

The compounds of the present disclosure may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention contemplates that all stereoisomeric forms of the compounds of formula (I), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, and mixtures thereof, such as racemic mixtures, are integral to the invention.

In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.

The compounds of formula (I) may exist in different tautomeric forms, and all such tautomers, such as those described herein, are included within the scope of the present invention.

The compounds of formula (I) 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 the other ingredients comprising the formulation and/or the mammal being treated therewith. In other embodiments, the salts need not be pharmaceutically acceptable salts and may be intermediates useful in the preparation and/or purification of compounds of formula (I) and/or in the isolation of enantiomers of compounds of formula (I).

Pharmaceutically acceptable acid addition salts may be formed by reaction of a compound of formula (I) with an inorganic or organic acid, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheyl salt, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, phosphate, Polysilonolactates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.

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

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, and the like.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of groups I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine, and tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable Salts.

In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms.

Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the general formula given in the present invention, except that one or more atoms are selected to haveAtomic substitution by atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I。

in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present³H、¹⁴C and¹⁸those compounds of F, or in which a non-radioactive isotope is present, e.g.²H and¹³C. the isotopically enriched compounds can be used for metabolic studies (use)¹⁴C) Reaction kinetics study (using, for example²H or³H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.¹⁸F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.

In addition, heavier isotopes are, in particular, deuterium (i.e.,²substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is to be considered as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has at least 3500 for each designated deuterium atom(52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D₂O, acetone-d₆、DMSO-d₆Those solvates of (a).

In another aspect, the invention relates to intermediates for the preparation of compounds of formula (I).

In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention. In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of pharmaceutically acceptable excipients, carriers, and vehicles. In other embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel, or spray dosage form.

In another aspect, the invention relates to a method of treating a disease or disorder modulated by JAK kinases, said method of treatment comprising administering to a mammal an effective amount of a compound or pharmaceutical composition disclosed herein. In some embodiments, the disease or disorder is selected from an inflammatory disease, an autoimmune disease, a metabolic disease, a destructive bone disease, a proliferative disease, an angiogenic disorder, sepsis, septic shock, shigellasis, a neurodegenerative disease, or retinitis.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention disclosed herein for the treatment of a disease or disorder selected from inflammatory diseases, autoimmune diseases, metabolic diseases, destructive bone diseases, proliferative diseases, angiogenic disorders, sepsis, septic shock, shigellasis, neurodegenerative diseases or retinitis.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the preparation of a medicament for the treatment of a disease or disorder selected from inflammatory diseases, autoimmune diseases, metabolic diseases, destructive bone diseases, proliferative diseases, angiogenic disorders, sepsis, septic shock, shigellasis, neurodegenerative diseases or retinitis.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention disclosed herein for the preparation of a medicament for inhibiting the activity of TYK2 kinase.

Pharmaceutical compositions, formulations and administration of the compounds of the invention

The present invention provides a pharmaceutical composition comprising a compound disclosed herein, or as listed in the examples; and at least one of pharmaceutically acceptable adjuvants, excipients, carriers, and solvents. The amount of compound in the pharmaceutical compositions disclosed herein is that amount which is effective to detect inhibition of a protein kinase in a biological sample or patient.

It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, if appropriate, in the form of a pharmaceutically acceptable derivative thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.

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

The term "pharmaceutically acceptable excipient" as used herein refers to a pharmaceutically acceptable material, mixture or vehicle, which is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and that would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected that facilitate the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected which may aid in the manufacture of stable dosage forms. Certain pharmaceutically acceptable excipients that facilitate carrying or transporting the disclosed compounds from one organ or portion of the body to another organ or portion of the body when administered to a patient may be selected. Certain pharmaceutically acceptable excipients may be selected that enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and may provide alternative functions, depending on how much of the excipient is present in the formulation and which other excipients are present in the formulation.

The skilled person is knowledgeable and skilled in the art to enable them to select suitable amounts of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there is a large amount of resources available to the skilled person, who describes pharmaceutically acceptable excipients and is used to select suitable pharmaceutically acceptable excipients. 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).

Various carriers for formulating pharmaceutically acceptable compositions, and well 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. Annu 1999, Marcel Dekker, New York, The contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the disclosed compounds, such as by producing any undesirable biological effect or interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

Thus, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a compound disclosed herein and at least one of a pharmaceutically acceptable adjuvant, excipient, carrier, vehicle, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the disclosed compounds may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, granules and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and lyophilized powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, e.g., suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.

In some embodiments, the compounds disclosed herein can be formulated in oral dosage forms. In other embodiments, the compounds disclosed herein may be formulated in an inhalation dosage form. In other embodiments, the compounds disclosed herein can be formulated for nasal administration. In still other embodiments, the compounds disclosed herein can be formulated for transdermal administration. In still other embodiments, the compounds disclosed herein may be formulated for topical administration.

The pharmaceutical compositions provided by the present invention may be provided as compressed tablets, milled tablets, chewable lozenges, fast-dissolving tablets, double-compressed tablets, or enteric-coated, sugar-coated or film-coated tablets. Enteric coated tablets are compressed tablets coated with a substance that is resistant to the action of gastric acid but dissolves or disintegrates 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 can help to mask unpleasant tastes or odors and prevent oxidation of the tablet. 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 are endowed with the same general characteristics as sugar coatings. A tabletted tablet is a compressed tablet prepared over more than one compression cycle, including a multi-layer tablet, and a press-coated or dry-coated tablet.

Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.

The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules, also known as Dry Fill 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. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those as described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention may be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be as described in U.S. patent nos.4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.

The pharmaceutical compositions provided herein may 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 dispersed throughout another in the form of globules, which can be either oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers and preservatives. Suspensions may include a pharmaceutically acceptable suspending agent and a preservative. The aqueous alcoholic solution may comprise pharmaceutically acceptable acetals, such as di (lower alkyl) acetals of lower alkyl aldehydes, e.g. acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may also contain preservatives. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for precise and convenient administration.

Other useful liquid and semi-solid dosage forms include, but are not limited to, those comprising the active ingredients provided herein and a secondary mono-or poly-alkylene glycol, including: 1, 2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further include one or more antioxidants, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

Dosage unit formulations for oral administration may be microencapsulated, where appropriate. They may also be prepared as extended or sustained release compositions, for example by coating or embedding the particulate material in a polymer, wax or the like.

The oral pharmaceutical composition provided by the invention can also be provided in the form of liposome, micelle, microsphere or nano system. Micellar dosage forms can be prepared using the methods described in U.S. Pat. No.6,350,458.

The pharmaceutical compositions provided herein can be provided as non-effervescent or effervescent granules and powders for reconstitution 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 sources of carbon dioxide.

Coloring and flavoring agents may be used in all of the above dosage forms.

The disclosed compounds may also be conjugated to soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the disclosed compounds may be combined with a class of biodegradable polymers used in achieving controlled release of a drug, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

The pharmaceutical compositions provided by the present invention may be formulated into immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.

The pharmaceutical compositions provided by the present invention may be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.

The pharmaceutical compositions provided by the present invention may be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solution or suspension in a liquid prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical Science (see Remington: The Science and Practice of Pharmacy, supra).

Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to inhibit microbial growth, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.

Suitable aqueous carriers include, but are not limited to: water, saline, normal saline or Phosphate Buffered Saline (PBS), sodium chloride injection, Ringers injection, isotonic glucose injection, sterile water injection, dextrose and lactated Ringers injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and the medium chain triglycerides of coconut oil, and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1, 3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N-dimethylacetamide, and dimethylsulfoxide.

Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurial, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl parabens, 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, phosphate and citrate. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate. Polyoxyethylene sorbitan monooleate 80 and triethanolamine oleate. Suitable sequestering 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 alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, and sulfobutyl ether 7-beta-cyclodextrin (f: (f))

CyDex,Lenexa,KS)。

The pharmaceutical compositions provided herein may be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials or syringes. The multi-dose parenteral formulation must contain a bacteriostatic or fungistatic concentration of the antimicrobial agent. All parenteral formulations must be sterile, as is known and practiced in the art.

In some embodiments, the pharmaceutical composition is provided as a ready-to-use sterile solution. In other embodiments, the pharmaceutical compositions are provided as sterile dried soluble products, including lyophilized powders and subcutaneous injection 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 still other embodiments, the pharmaceutical composition is formulated as a sterile, dry, insoluble product that is reconstituted with a carrier prior to use. In some embodiments, the pharmaceutical composition is formulated as a sterile emulsion ready for use.

The disclosed pharmaceutical compositions may be formulated into immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

The pharmaceutical composition may be formulated as a suspension, solid, semi-solid, or thixotropic liquid for depot administration for implantation. In some embodiments, the disclosed pharmaceutical compositions are dispersed in a solid internal matrix surrounded by an outer polymeric membrane that is insoluble in body fluids but allows diffusion therethrough of the active ingredient in the pharmaceutical composition.

Suitable internal matrices include polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrogels of hydrophilic polymers such as esters of acrylic and methacrylic acid, collagen, crosslinked polyvinyl alcohol, and partially hydrolyzed polyvinyl acetate of the class of copolymers.

Suitable outer polymeric films include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene, polyvinyl chloride, copolymers of chlorinated ethylene and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomers polyethylene terephthalate, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymers, ethylene/vinyl acetate/vinyl alcohol terpolymers, and ethylene/ethyleneoxyethanol copolymers.

In another aspect, the disclosed pharmaceutical compositions may be formulated in any dosage form suitable for administration to a patient by inhalation, such as a dry powder, aerosol, suspension, or solution composition. In some embodiments, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient as a dry powder. In still other embodiments, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient via a nebulizer. Dry powder compositions for delivery to the lung by inhalation typically comprise a finely powdered compound of the disclosed invention and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that are 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 may be prepared, for example, by micronization and milling. Generally, the size-reduced (e.g., micronized) compound may pass through a D of about 1 to 10 microns₅₀Values (e.g., measured by laser diffraction).

Aerosols can be formulated by suspending or dissolving the disclosed compounds 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-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane and pentane. Aerosols comprising the compounds disclosed herein are typically administered to a patient via a Metered Dose Inhaler (MDI). Such devices are known to those skilled in the art

The aerosol may contain additional pharmaceutically acceptable excipients that may be used by MDIs, such as surfactants, lubricants, co-solvents, and other excipients, to improve the physical stability of the formulation, to improve valve characteristics, to improve solubility, or to improve taste.

Pharmaceutical compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch agent by iontophoresis, as generally described in Pharmaceutical Research,3(6),318 (1986).

Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams and gels may be formulated with a water or oil base, and suitable thickeners and/or gelling agents and/or solvents. Such bases 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 according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifiers.

Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.

Powders for external use may be formed in the presence of any suitable powder base, for example talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base containing one or more dispersing agents, solubilising agents, suspending agents or preservatives.

Topical formulations may be administered by application to the affected area one or more times per day; an occlusive dressing covering the skin is preferably used. Adhesive depot systems allow for continuous or extended administration.

For treatment of the eye, or other organs such as the mouth and skin, the composition may be applied as a topical ointment or cream. When formulated as an ointment, the disclosed compounds may be used with a paraffinic or water soluble ointment base. Alternatively, the disclosed compounds may be formulated as a cream with an oil-in-water cream base or an oil-in-water base.

Use of the Compounds and compositions of the invention

The present invention provides the use of the compounds and pharmaceutical compositions disclosed herein for the treatment, prevention or amelioration of diseases or disorders mediated or otherwise affected by TYK2 kinase, in particular for the manufacture of a medicament for the treatment or prevention of inflammatory diseases, autoimmune diseases, metabolic diseases, destructive bone diseases, proliferative diseases, angiogenic disorders, sepsis, septic shock, shigellasis or neurodegenerative diseases or retinitis.

In particular, the invention provides a class of compounds disclosed herein or pharmaceutical compositions comprising a compound disclosed herein for use in the treatment, prevention or amelioration of a disease or disorder mediated or otherwise affected by inappropriate TYK2 kinase activity or a disease or disorder mediated or otherwise affected by inappropriate TYK2 kinase activity, selected from inflammatory diseases, autoimmune metabolic diseases, destructive bone diseases, proliferative diseases, angiogenic disorders, sepsis, septic shock, shigellation disease or neurodegenerative diseases or retinitis.

In some embodiments, such diseases or disorders include, but are not limited to: pancreatitis, asthma, allergy, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, discoid lupus erythematosus, scleroderma, chronic thyroiditis, Gray's disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory response, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Nett's syndrome, gout, traumatic arthritis, rheumatoid arthritis, acute synovitis, chronic inflammatory bowel disease, rheumatoid arthritis, chronic inflammatory bowel disease, autoimmune gastritis, autoimmune thrombocytopenia, atopic dermatitis, chronic inflammatory bowel disease, chronic inflammatory arthritis, chronic obstructive pulmonary tuberculosis, chronic inflammatory arthritis, chronic obstructive pulmonary arthritis, chronic inflammatory arthritis, chronic obstructive pulmonary arthritis, chronic inflammatory arthritis, chronic obstructive pulmonary arthritis, chronic inflammatory arthritis, Pancreatic beta cell disease, a disease characterized by massive neutrophil infiltration, rheumatoid spondylitis, gouty arthritis, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, allograft rejection, fever due to infection, myalgia due to infection, cachexia secondary to infection, keloid formation, scar tissue formation, fever, influenza, osteoporosis, osteoarthritis, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, Shigella's disease, Alzheimer's disease, cerebral ischemia or neurodegenerative diseases caused by traumatic injury, angiogenic disorders, CMV retinitis, AIDS, ARC, herpes, stroke, viral diseases, inflammatory bowel disease, stroke, myocardial ischemia, ischemia in stroke heart attack, organ hypoxia, vascular proliferation, cardiac reperfusion injury, renal reperfusion injury, thrombosis, cardiac hypertrophy, coagulation-induced enzymatic platelet aggregation, endotoxemia, toxic shock syndrome, prostaglandin endoperoxidase synthase-2-associated disease state, or pemphigus vulgaris.

In another aspect, the present invention provides a method of treating a mammal suffering from or at risk of suffering from a disease disclosed herein, comprising administering a condition treating effective amount or a condition preventing effective amount of one or more of the pharmaceutical compositions or compounds disclosed herein.

In one method of therapeutic aspects, the invention provides a method of treating and/or preventing a mammal susceptible to or suffering from a TYK 2-mediated disease, comprising administering a therapeutically effective amount or a prophylactically effective amount of one or more of the pharmaceutical compositions or compounds disclosed herein. In particular examples, the TYK 2-mediated disease is selected from an inflammatory disease, an autoimmune disease, a metabolic disease, a destructive bone disease, a proliferative disease, an angiogenic disorder, sepsis, septic shock, shigellasis, a neurodegenerative disease, or retinitis.

In another aspect, provided herein is a class of compounds disclosed herein, or a pharmaceutical composition comprising a compound disclosed herein, for use in the preparation of a medicament for the treatment or prevention of a TYK 2-mediated disease. In particular examples, the TYK 2-mediated disease is selected from an inflammatory disease, an autoimmune disease, a metabolic disease, a destructive bone disease, a proliferative disease, an angiogenic disorder, sepsis, septic shock, shigellosis, a neurodegenerative disease, or retinitis.

In another aspect, provided herein is a method of treating and/or preventing a mammal susceptible to or suffering from an inflammatory disease, autoimmune disease, or autoimmune disease, comprising administering a therapeutically effective amount or a prophylactically effective amount of one or more of the pharmaceutical compositions or compounds disclosed herein. In particular examples, the inflammatory disease is selected from, but not limited to, crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allograft rejection, or chronic obstructive pulmonary disease; autoimmune diseases are selected from, but not limited to, Gray's disease, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus, lupus nephritis, discoid lupus erythematosus or psoriasis; the auto-inflammatory disease is selected from, but not limited to, CAPS, TRAPS, FMF, adult still's disease, systemic juvenile idiopathic arthritis, gout, or gouty arthritis.

Method of treatment

In some embodiments, the presently disclosed methods of treatment comprise administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. Various embodiments of the present disclosure include methods of treating the above-mentioned diseases by administering to a patient in need thereof a safe and effective amount of a disclosed compound or a pharmaceutical composition comprising a disclosed compound.

In some embodiments, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds may be administered by any suitable route of administration, including systemic and topical administration. Systemic administration includes oral, parenteral, transdermal and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin and intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, a disclosed compound or a pharmaceutical composition comprising a disclosed compound may be administered orally. In other embodiments, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds may be administered by inhalation. In yet another embodiment, the presently disclosed compounds or compositions comprising the presently disclosed compounds may be administered intranasally.

In some embodiments, a disclosed compound or a pharmaceutical composition comprising a disclosed compound may be administered once or several times at different time intervals over a specified period of time according to a dosing regimen. For example, once, twice, three times or four times daily. In some embodiments, the administration is once daily. In yet other embodiments, the administration is twice daily. The administration may be carried out until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds depend on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by the skilled person. In addition, suitable dosing regimens for the compounds or pharmaceutical compositions comprising the disclosed compounds, including the duration of the regimen, will depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that appropriate dosage regimens may be required to be adjusted for the individual patient's response to the dosage regimen, or as the individual patient needs to change over time.

The compounds disclosed herein may be administered simultaneously, or before or after, one or more other therapeutic agents. The compounds of the invention may be administered separately from the other therapeutic agents, by the same or different routes of administration, or in the same pharmaceutical composition.

The disclosed pharmaceutical compositions and combinations may be in unit dosage forms containing from about 1 to about 1000mg, or from about 1 to about 500mg of the active ingredient for an individual of from about 50 to about 70 kg. The therapeutically effective amount of the compound, pharmaceutical composition or combination thereof will depend upon the species, weight, age and condition of the individual to whom it is administered, the disorder or disease being treated (disease) or its severity. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of the disorder or disease.

The above cited dose profiles have been demonstrated in vitro and in vivo tests using beneficial mammals (e.g., mice, rats, dogs, monkeys) or isolated organs, tissues and specimens thereof. The compounds disclosed herein are used in vitro in the form of solutions, e.g. aqueous solutions, and also enterally, parenterally, especially intravenously, in vivo, e.g. in the form of suspensions or aqueous solutions.

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

In addition, the compounds disclosed herein may be administered in the form of a prodrug. In the present invention, a "prodrug" of a disclosed compound is a functional derivative that, when administered to a patient, is ultimately released in vivo. When administering the compounds disclosed herein in the form of a prodrug, one skilled in the art can practice one or more of the following: (a) altering the in vivo onset time of the compound; (b) altering the duration of action of the compound in vivo; (c) altering the in vivo delivery or distribution of the compound; (d) altering the in vivo solubility of the compound; and (e) overcoming side effects or other difficulties faced by the compounds. Typical functional derivatives useful for preparing prodrugs comprise variants of the compounds which are cleaved in vivo either chemically or enzymatically. These variants, which involve the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.

General synthetic procedure

To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

In the examples described below, all temperatures are given in degrees celsius unless otherwise indicated. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.

¹H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer.¹H NMR Spectrum in CDC1₃、D₂O、DMSO-d₆、CD₃OD or acetone-d₆TMS (0ppm) or chloroform (7.26ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), ddd (doublet of doublets), dddd (doublet of doublets), dt (doublet of triplets), tt (triplet of triplets). Coupling constant J, expressed in Hertz (Hz).

The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-M (column model: Zorbax SB-C18, 2.1X 30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase 5% -95% (CH with 0.1% formic acid)₃CN) in (H containing 0.1% formic acid)₂O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.

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

The following acronyms are used throughout the invention:

h hr mL/mL

mu.L of DMF N, N-dimethylformamide

CDCl₃Deuterated chloroform MPa

DMSO dimethyl sulfoxide NaCl sodium chloride

DMSO-d₆Deuterated dimethyl sulfoxide HClHydrochloric acid

g Pd₂(dba)₃Tris (dibenzylideneacetone) dipalladium

mg of Xantphos 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene

M mol of H per liter₂O water

mM millimole per liter EDTA ethylenediaminetetraacetic acid

molar hepes 4-hydroxyethyl piperazine ethanesulfonic acid

mmol millimole

The following reaction scheme describes the steps for preparing the compounds of the present invention. Each X, Y, V unless otherwise stated¹、V²、V³、V⁴、R¹、R⁶And R⁷Having the definitions as described in the present invention.

Reaction scheme 1

Formula (A), (B) and5) The compounds shown can be prepared by this reaction scheme 1: formula (A), (B) and1) The compound reacts under the action of sodium borohydride to obtain a compound shown in a formula (I)2) The compounds shown. Formula (A), (B) and2) A compound of the formula3) The compound is reacted under the action of n-butyl lithium to obtain a compound shown in a formula (I)4) The compounds shown. Formula (A), (B) and4) The compound reacts under the action of sodium bis (trimethylsilyl) amide and methyl benzene sulfonyl chloride to obtain a compound shown in a formula (I)5) The compounds shown.

Reaction scheme 2

Formula (A), (B) and8) The compounds shown can be prepared by this reaction scheme 2: formula (A), (B) and6) The compound reacts under the action of m-chloroperoxybenzoic acid to obtain a compound shown in the formula (I)7) The compounds shown. Formula (A), (B) and7) The compound reacts under the action of phosphorus oxychloride to obtain a compound shown in a formula (A)8) The compounds shown.

Reaction scheme 3

Formula (A), (B) and12) The compounds shown can be prepared by this reaction scheme 3: formula (A), (B) and8) A compound of the formula9) The compound is shown in Pd₂(dba)₃Xantphos and cesium carbonate to obtain a compound of the formula10) The compounds shown. Formula (A), (B) and10) A compound of the formula11) The compound is shown in Pd₂(dba)₃Xantphos and cesium carbonate to obtain a compound of the formula12) The compounds shown.

The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.

Examples

Example 1N- (1- (4 '-methoxy-4, 5-dihydro-2H, 5' H-spiro [ furan-3, 7 '-furo [3,4-b ] pyridin ] -2' -yl) -1H-pyrrolo [3,2-c ] pyridin-6-yl) cyclopropylcarboxamide

First step synthesis of (2-bromopyridin-3-yl) -methanol

Adding 2-bromo-3-aldehyde pyridine (5.58g,30.0mmol) and anhydrous methanol (60mL) into a reaction bottle, stirring to dissolve, cooling to 0 ℃ under the protection of nitrogen, adding sodium borohydride (1.38g,35.7mmol) twice, heating to room temperature, and stirring to react for 0.5 h. The reaction was quenched by the addition of saturated ammonium chloride (50mL), methanol was removed by rotary evaporation under reduced pressure, extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with saturated sodium chloride (50mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated under reduced pressure, and dried under vacuum at 50 ℃ to give the title compound as a white solid (5.47g, yield 97.0%).

MS(ESI,pos.ion)m/z:188.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.35–8.23(m,1H),7.91–7.80(m,1H),7.38–7.30(m,1H),4.77(d,J＝5.9Hz,2H),2.38(t,J＝6.0Hz,1H).

Second step Synthesis of 3- (3- (hydroxymethyl) pyridin-2-yl) tetrahydrofuran-3-ol

Adding (2-bromopyridin-3-yl) -methanol (1.13g,6.01mmol) and anhydrous toluene (10mL) into a reaction flask, evaporating to dryness under reduced pressure, adding anhydrous tetrahydrofuran (30mL), cooling to-78 ℃, dropwise adding n-butyllithium (2.5mol/L n-hexane solution, 4.9mL,12mmol), stirring at 78 ℃ for 1h, adding tetrahydrofuran-3-ketone (0.62g,7.2mmol), stirring for 2h, then heating to room temperature, continuing to stir for 30min, adding saturated ammonium chloride (30mL) to quench the reaction, extracting with ethyl acetate (30 mL. times.3), combining organic phases, washing with saturated sodium chloride (30mL), collecting the organic phase, drying with anhydrous sodium sulfate, filtering, evaporating the filtrate under reduced pressure, purifying the obtained residue by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/4), the title compound was obtained as a viscous colorless oily liquid (0.21g, yield 17.9%).

MS(ESI,pos.ion)m/z:196.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.54–8.40(m,1H),8.53–8.40(m,1H),7.86–7.73(m,1H),7.32–7.22(m,1H),4.89–4.70(m,2H),4.33–4.24(m,1H),4.19–4.11(m,2H),4.07–3.88(m,2H),2.68–2.54(m,1H),2.37–2.21(m,1H).

Step three, synthesis of 4, 5-dihydro-2H, 5 'H-spiro [ furan-3, 7' -furo [3,4-b ] pyridine ]

Adding 3- (3- (hydroxymethyl) pyridyl-2-yl) tetrahydrofuran-3-ol (154.0mg,0.79mmol) and anhydrous toluene (5mL) into a reaction flask, evaporating to dryness under reduced pressure, adding anhydrous tetrahydrofuran (8mL), cooling to 0 ℃, dropwise adding a tetrahydrofuran solution of sodium bis (trimethylsilyl) amide (2mol/L, 0.87mL,1.7mmol), stirring at 0 ℃ for 10min, adding p-toluenesulfonyl chloride (184.0mg,0.95mmol), continuing to stir for 1h, adding saturated ammonium chloride (10mL) to quench the reaction, extracting with ethyl acetate (10 mL. times.3), combining organic phases, washing with saturated sodium chloride (10mL), filtering, evaporating the filtrate to dryness, purifying the obtained residue by reduced pressure column chromatography (dichloromethane/methanol (v/v) ═ 19/1), the title compound was obtained as a yellow oily liquid (108.0mg, yield 77.3%).

MS(ESI,pos.ion)m/z:178.1[M+H]⁺；

The fourth step of Synthesis of 4, 5-dihydro-2H, 5' H-spiro [ furan-3, 7' -furo [3,4-b ] pyridine ]1' -oxide

4, 5-dihydro-2H, 5 'H-spiro [ furan-3, 7' -furo [3,4-b ] pyridine ] (80.0mg,0.45mmol), dichloromethane (5mL) and m-chloroperoxybenzoic acid (137.0mg,0.67mmol) were added to a reaction flask, the reaction was stirred at room temperature for 4 hours, saturated sodium sulfite (5mL) was added to quench the reaction, saturated sodium carbonate (5mL) was added, chloroform (10mL × 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 19/1) to give the title compound as a white solid (50.0mg, yield 57.3%).

MS(ESI,pos.ion)m/z:194.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.10(d,J＝6.4Hz,1H),7.25–7.20(m,1H),7.13(d,J＝7.6Hz,1H),5.09(s,2H),4.39(d,J＝9.3Hz,1H),4.19–4.09(m,2H),3.87(d,J＝9.3Hz,1H),3.09–2.95(m,1H),2.15–2.00(m,1H).

Fifth step Synthesis of 4' -chloro-4, 5-dihydro-2H, 5' H-spiro [ furan-3, 7' -furo [3,4-b ] pyridine ]

4, 5-dihydro-2H, 5' H-spiro [ furan-3, 7' -furo [3,4-b ] pyridine ]1' -oxide (294.0mg,1.52mmol) and phosphorus oxychloride (5mL,53.6mmol) were added to a reaction flask, the mixture was heated to 110 ℃ and stirred for reaction for 5 hours, the reaction solution was evaporated to dryness under reduced pressure, saturated sodium carbonate (5mL) and water (5mL) were added, ethyl acetate (10mL × 3) was extracted, the organic phases were combined, washed with saturated sodium chloride (10mL), dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness under reduced pressure, and the obtained residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 49/1) to give the title compound as an off-white solid (180.0mg, yield 56.0%).

MS(ESI,pos.ion)m/z:194.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.43(d,J＝5.4Hz,1H),7.20(d,J＝5.4Hz,1H),5.12(s,2H),4.13(dd,J＝8.6,5.5Hz,2H),4.01(q,J＝9.9Hz,2H),2.49–2.36(m,1H),2.35–2.23(m,1H).

Sixth step Synthesis of 4' -methoxy-4, 5-dihydro-2H, 5' H-spiro [ furan-3, 7' -furo [3,4-b ] pyridine ]

4' -chloro-4, 5-dihydro-2H, 5' H-spiro [ furan-3, 7' -furo [3,4-b ] pyridine ] (20.0mg,0.0945mmol) and a methanol solution of sodium methoxide (2mL,11mmol,5.4mol/L) were added to a reaction flask, the reaction was stirred at 80 ℃ for 4 hours, saturated ammonium chloride (5mL) was added to quench the reaction, the pH was adjusted to weak alkalinity with concentrated hydrochloric acid, ethyl acetate (10 mL. times.3) was extracted, the organic phases were combined, saturated sodium chloride (10mL) was washed, and the organic phase was evaporated to dryness under reduced pressure to give the title compound as a white solid (19.0mg, 97.0% yield).

MS(ESI,pos.ion)m/z:208.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.43(d,J＝5.7Hz,1H),6.69(d,J＝5.7Hz,1H),5.06(s,2H),4.12(dd,J＝8.7,5.5Hz,2H),4.02–3.94(m,2H),3.89(s,3H),2.51–2.34(m,1H),2.31–2.17(m,1H).

Seventh step Synthesis of 4 '-methoxy-4, 5-dihydro-2H, 5' H-spiro [ furan-3, 7 '-furo [3,4-b ] pyridine ]1' -oxide

4' -methoxy-4, 5-dihydro-2H, 5' H-spiro [ furan-3, 7' -furo [3,4-b ] pyridine ] (158.0mg,0.76mmol), anhydrous dichloromethane (5mL) and m-chloroperoxybenzoic acid (232.0mg,1.14mmol) were charged into a reaction flask, stirred at room temperature overnight, quenched with saturated sodium sulfite (5mL), stirred for 15min, then saturated sodium carbonate (5mL), chloroform (10mL × 3) extracted, the organic phases combined, dried over anhydrous sodium sulfate, filtered, the filtrate evaporated to dryness under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 19/1) to give the title compound as a white solid (124.0mg, yield 72.9%).

MS(ESI,pos.ion)m/z:224.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.07(d,J＝7.0Hz,1H),6.72(d,J＝7.0Hz,1H),5.09–4.99(m,2H),4.43(d,J＝9.2Hz,1H),4.19–4.04(m,2H),3.89(s,3H),3.86(d,J＝9.3Hz,1H),3.12–2.97(m,1H),2.13–2.00(m,1H).

Eighth step Synthesis of 2 '-chloro-4' -methoxy-4, 5-dihydro-2H, 5 'H-spiro [ furan-3, 7' -furo [3,4-b ] pyridine ]

4 '-methoxy-4, 5-dihydro-2H, 5' H-spiro [ furan-3, 7 '-furo [3,4-b ] pyridine ]1' -oxide (90.0mg,0.40mmol) and phosphorus oxychloride (6mL,64.37mmol) were added to a reaction flask, the reaction was stirred at 110 ℃ for 10H, the system was dried, saturated sodium carbonate (5mL) and water (5mL) were added, ethyl acetate (10mL × 3) was extracted, the organic phases were combined, saturated sodium chloride (10mL) was washed, dried, filtered, the solution was evaporated to dryness under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 19/1) to give the title compound as an off-white solid (35.0mg, yield 36.0%).

MS(ESI,pos.ion)m/z:242.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)6.72(s,1H),5.01(s,2H),4.10(dd,J＝8.8,5.4Hz,2H),4.02–3.93(m,2H),3.90(s,3H),2.49–2.36(m,1H),2.28–2.17(m,1H).

Ninth step Synthesis of 2'- (6-chloro-1H-pyrrolo [3,2-c ] pyridin-1-yl) -4' -methoxy-4, 5-dihydro-2H, 5 'H-spiro [ furan-3, 7' -furo [3,4-b ] pyridine ]

2 '-chloro-4' -methoxy-4, 5-dihydro-2H, 5 'H-spiro [ furan-3, 7' -furo [3,4-b ] is added into a reaction bottle in sequence]Pyridine compound](0.14g,0.58mmol), 6-chloro-1H-pyrrolo [3, 2-c)]Pyridine (0.11g,0.70mmol), cesium carbonate (0.38g,1.16mmol), Pd₂(dba)₃(0.11g,0.12mmol), xanthphos (0.067g,0.12mmol) and dioxane (10mL), stirred overnight at 130 ℃ under nitrogen, the reaction was evaporated to dryness under reduced pressure, and the resulting residue was purified by column chromatography (methanol/dichloromethane ═ 1/20) to give the title compound as a yellow solid (0.10g, yield 48.3%).

MS(ESI,pos.ion)m/z:358.1[M+H]⁺.

Tenth step Synthesis of N- (1- (4 '-methoxy-4, 5-dihydro-2H, 5' H-spiro [ furan-3, 7 '-furo [3,4-b ] pyridin ] -2' -yl) -1H-pyrrolo [3,2-c ] pyridin-6-yl) cyclopropylcarboxamide

2' - (6-chloro-1H-pyrrole [3, 2-c) is added into a reaction bottle in sequence]Pyridin-1-yl) -4' -methoxy-4, 5-dihydro-2H, 5' H-spiro [ furan-3, 7' -furo [3,4-b]Pyridine compound](85.0mg,0.24mmol), acetamide (30.0mg,0.36mmol), cesium carbonate (0.15g,0.47mmol), Pd₂(dba)₃(43.9mg,48.0mmol), xanthphos (27.8mg,48.0mmol) and dioxane (10mL), under nitrogen, heated to 130 ℃, stirred for reaction overnight, the reaction solution was evaporated to dryness under reduced pressure, and the resulting residue was purified by column chromatography (methanol/dichloromethane (v/v) ═ 1/20) to give the title compound as a yellow solid (60.0mg, yield 62.1%).

MS(ESI,pos.ion)m/z:407.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):10.65(s,1H),9.18(s,1H),8.63(s,1H),8.09(d,J＝3.5Hz,1H),7.22(s,1H),6.83(d,J＝3.4Hz,1H),5.03(s,2H),4.04–3.84(m,7H),2.53(d,J＝8.4Hz,1H),2.24–2.15(m,1H),2.05–1.98(m,1H),0.78(d,J＝7.2Hz,4H).

¹³C NMR(151MHz,DMSO-d₆)δ(ppm):172.4,162.9,160.9,155.1,147.8,141.5,140.9,128.19,123.8,117.6,104.7,99.1,97.5,93.6,77.1,68.3,67.8,56.8,14.7,7.9,7.9.

Biological assay

The LC/MS/MS system for analysis included an Agilent 1200 series vacuum degassing furnace, a binary injection pump, an orifice plate autosampler, a column oven, an Agilent G6430 three-stage quadrupole mass spectrometer with an electrospray ionization (ESI) source. The quantitative analysis was performed in MRM mode, with the parameters of the MRM transition as shown in table a:

TABLE A

Multiple reaction detection scan	490.2→383.1
		Fragmentation voltage	230V
Capillary voltage	55V
		Temperature of drying gas	350℃
Atomizer	0.28MPa
		Flow rate of drying gas	10L/min

Analysis 5. mu.L of sample was injected using an Agilent XDB-C18, 2.1X 30mm, 3.5. mu.M column. Analysis conditions were as follows: the mobile phase was 0.1% aqueous formic acid (A) and 0.1% methanolic formic acid (B). The flow rate was 0.4 mL/min. Mobile phase gradients are shown in table B:

TABLE B

Time	Gradient of mobile phase B
		0.5min	5％
1.0min	95％
		2.2min	95％
2.3min	5％
		5.0min	Terminate

Also used for the analysis was an Agilent 6330 series LC/MS spectrometer equipped with a G1312A binary syringe pump, a G1367A auto sampler and a G1314C UV detector; the LC/MS/MS spectrometer uses an ESI radiation source. The appropriate cation model treatment and MRM conversion for each analyte was performed using standard solutions for optimal analysis. During the analysis a Capcell MP-C18 column was used, with the specifications: 100x4.6mm I.D., 5 μ M (Phenomenex, Torrance, California, USA). The mobile phase was 5mM ammonium acetate, 0.1% aqueous methanol (a): 5mM ammonium acetate, 0.1% methanolic acetonitrile solution (B) (70/30, v/v); the flow rate is 0.6 mL/min; the column temperature was kept at room temperature; 20 μ L of sample was injected.

Example A stability in human and rat liver microsomes

The stability of the compounds of the invention in human and rat liver microsomes can be tested by the following two methods:

the method comprises the following steps:

human or rat liver microsomes were incubated in polypropylene tubes in duplicate wells. A typical incubation mixture comprises human or rat liver microsomes (0.5mg protein/mL), the compound of interest (5. mu.M) and a total volume of 200. mu.L of NADPH (1.0mM) potassium phosphate buffer (PBS, 100mM, pH 7.4), dissolved in DMSO, and diluted with PBS to a final DMSO solution concentration of 0.05%. And incubated in a water bath at 37 ℃ in air communication, and after 3 minutes of pre-incubation, protein was added to the mixture and the reaction was started. At different time points (0, 5, 10, 15, 30 and 60min), the reaction was stopped by adding the same volume of ice-cold acetonitrile. The samples were stored at-80 ℃ until LC/MS/MS analysis.

The linear concentration range of each target compound was determined, and then the concentration of the target compound in the human or rat liver microsome incubation mixture was determined by the LC/MS method.

Parallel incubation experiments were performed using denatured microsomes as negative control and dextromethorphan (70 μm) as positive control. Negative control, incubation at 37 ℃ and reaction termination at different time points (0,15 and 60 min); positive controls, incubated at 37 ℃ and reactions 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 microsomal incubation system.

The method 2 comprises the following steps:

in addition, stability data for the compounds of the invention in human or rat liver microsomes can also be obtained from the following assays:

human or rat liver microsomes were incubated in duplicate wells in polypropylene tubes. A typical incubation mixture comprises human or rat liver microsomes (final concentration: 0.5mg protein/mL), the compound of interest (final concentration: 1.5. mu.M) and a total volume of 30. mu.L of K-buffer solution (containing 1.0mM EDTA,100mM, pH 7.4). Compounds were dissolved in DMSO and diluted with K-buffer to give a final DMSO concentration of 0.2%. After a pre-incubation time of 10 minutes, 15. mu.L of NADPH (final concentration: 2mM) was added for the enzymatic reaction, and the whole assay was carried out in an incubation tube at 37 ℃. At various time points (0,15, 30 and 60 minutes), the reaction was stopped by the addition of 135. mu.L acetonitrile (containing IS). The supernatant was collected by centrifugation at 4000rpm for 10 minutes to remove protein and analyzed by LC-MS/MS.

In the above assay, ketanserin (1 μ M) was selected as a positive control, incubated at 37 ℃ and the reaction was terminated at different time points (0,15, 30 and 60 min). A positive control sample was included in each assay method to ensure the integrity of the microsomal incubation system.

Data analysis

For each reaction, the concentration of compound (in percent) in human or rat liver microsome incubations was plotted as a percentage of the zero time point to infer intrinsic hepatic clearance CL in vivo_int(ref.:Naritomi Y,Terashita S,Kimura S,Suzuki A,Kagayama A,Sugiyama Y.Prediction of human hepatic 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.)。

It is experimentally shown that the compounds of the invention exhibit suitable stability when incubated in human and rat liver microsomes.

Example B pharmacokinetics of mice, rats, dogs and monkeys after intravenous and oral dosing of a compound of the invention Evaluation of science

The present invention evaluates the pharmacokinetic studies of the compounds of the invention in mice, rats, dogs or monkeys. The compounds of the invention were administered as aqueous solutions or 2% HPMC + 1% Tween-80 in water, 5% DMSO + 5% saline solution, 4% MC or in capsule form. For intravenous administration, animals are given a dose of about 0.5, 0.6, 1, or 2 mg/kg. For oral doses (p.o.), rats and mice were 5 or 10mg/kg, and dogs and monkeys were 10 mg/kg. Blood (0.3mL) was taken 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 at3,000 or 4,000rpm for 10 minutes. The plasma solutions were collected and stored at-20 ℃ or-70 ℃ until the LC/MS/MS analysis described above was performed. The results show that the compounds provided by the invention show good pharmacokinetic properties including better absorption and good oral bioavailability when administered intravenously or orally.

As can be seen from experiments, when the compound provided by the invention is administered by intravenous injection or oral administration, the compound provided by the invention shows good pharmacokinetic properties, including better Absorption (AUC)_last) And good oral bioavailability (F).

Example C kinase Activity assay

The utility of the disclosed compounds as protein kinase inhibitors can be evaluated by the following experiments.

General description of kinase assays

Kinase assays by detecting incorporation of gamma-³³Myelin Basic Protein (MBP) of P-ATP. Mu.g/ml MBP (Sigma # M-1891) Tris buffered saline (TBS; 50mM Tris pH 8.0,138mM NaCl,2.7mM KCl) was prepared in 60. mu.L/well in high binding white 384 well plates (Greiner). Incubate at 4 ℃ for 24 h. The plate was then washed 3 times with 100. mu.L TBS. Kinase reaction in a total volume of 34. mu.L of kinase buffer (5mM Hepes pH 7.6,15mM NaCl, 0.01% bovine serum albumin (Sigma # I-5506),10mM MgCl₂1mM DTT, 0.02% TritonX-100). Compounds were dissolved in DMSO and added to each well at a final DMSO concentration of 1%. Each data was assayed in two passes, with at least two trials for each compound assay. For example, the final concentration of the enzyme is 10nM or 20 nM. Addition of unlabeled ATP (10. mu.M) and gamma-³³P-labelled ATP (2X 10 per well)⁶cpm, 3000Ci/mmol) was started. The reaction was performed at room temperature with shaking for 1 hour. The 384 well plates were washed with 7 × PBS and 50 μ L of scintillation fluid per well was added. The results were checked with a Wallac Trilux counter. It will be apparent to those skilled in the art that this is only one of many detection methods, and that other methods are possible.

IC inhibited by the test method₅₀And/or suppression constant K_i。IC₅₀Defined as the concentration of compound that inhibits 50% of the enzyme activity under the conditions tested. IC was estimated using a dilution factor of 1/2log to generate a curve containing 10 concentration points₅₀Values (e.g., a typical curve is made by the concentration of compound: 3. mu.M, 1. mu.M, 0.3. mu.MM、0.1μM、0.03μM、0.01μM、0.003μM、0.001μM、0.0003μM、0μM)。

JAK1(h)

JAK1(h) in 20mM Tris/HCl pH 7.5, 0.2mM EDTA, 500. mu. M GEEPLYWSFPAKKK, 10mM magnesium acetate and [ gamma-³³P-ATP](specific activity about 500cpm/pmol, 10. mu.M or K_MValue) is present. The reaction was started after the addition of the MgATP mixture. After incubation at room temperature for 40 minutes, a 3% phosphoric acid solution was added thereto to terminate the reaction. 10 μ L of the reaction solution was spotted on a P30 filter and washed 3 times with 75mM phosphoric acid in 5 minutes and stored in methanol solution immediately before drying and scintillation counting.

JAK2(h)

JAK2(h) at 8mM MOPS pH 7.0, 0.2mM EDTA, 100. mu. M KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC, 10mM magnesium acetate and [ gamma-³³P-ATP](specific activity about 500cpm/pmol, 10. mu.M or K_MValue) is present. The reaction was started after the addition of the MgATP mixture. After incubation at room temperature for 40 minutes, a 3% phosphoric acid solution was added thereto to terminate the reaction. 10 μ L of the reaction solution was spotted on a P30 filter and washed 3 times with 75mM phosphoric acid in 5 minutes and stored in methanol solution immediately before drying and scintillation counting.

JAK3(h)

JAK3(h) at 8mM MOPS pH 7.0, 0.2mM EDTA, 500. mu. M GGEEEEYFELVKKKK, 10mM magnesium acetate and [ gamma-³³P-ATP](specific activity about 500cpm/pmol, 10. mu.M or K_MValue) is present. The reaction was started after the addition of the MgATP mixture. After incubation at room temperature for 40 minutes, a 3% phosphoric acid solution was added thereto to terminate the reaction. 10 μ L of the reaction solution was spotted on a P30 filter and washed 3 times with 75mM phosphoric acid in 5 minutes and stored in methanol solution immediately before drying and scintillation counting.

TYK2(h)

TYK2(h) at 8mM MOPS pH 7.0, 0.2mM EDTA, 250. mu. M GGMEDIYFEFMGGKKK,10mM magnesium acetate and [ gamma-³³P-ATP](specific activity about 500cpm/pmol, 10. mu.M or K_MValue) is present. Adding intoThe reaction was started after the MgATP mixture. After incubation at room temperature for 40 minutes, a 3% phosphoric acid solution was added thereto to terminate the reaction. 10 μ L of the reaction solution was spotted on a P30 filter and washed 3 times with 75mM phosphoric acid in 5 minutes and stored in methanol solution immediately before drying and scintillation counting.

The kinase assay of the present invention was performed by Millipore corporation, UK (Millipore UK Ltd, Dundee Technology Park, Dundee DD 21 SW, UK).

Alternatively, the kinase activity of the compound may be measured by KINOMEscan^TMDetection, based on the quantitative detection of compounds using an active site-directed competitive binding assay. The test is carried out by combining with three compounds, namely DNA marker enzyme, immobilized ligand and detection compound, and qPCR is carried out by DNA marker to detect the competitive capacity of the compound and the immobilized ligand.

Most experiments were carried out by culturing a kinase-labeled T7 bacteriophage strain in an E.coli host derived from BL21 strain, infecting E.coli in the logarithmic growth phase with T7 bacteriophage, incubating with shaking at 32 ℃ until lysis, centrifuging the lysate to remove cell debris, transferring the remaining kinase to HEK-293 cells, and carrying out qPCR detection with DNA labeling. Streptavidin-coated particles were treated with biotinylated small molecule ligands for 30min at room temperature to generate affinity resins for kinase assays. The ligand particles are blocked by surplus biotin and then passed through blocking Solution (SEABLOCK)^TM(Pierce), 1% bovine serum albumin, 0.05% Tween-20, 1mM DTT) washes unbound ligand to reduce non-specific binding. By binding buffer (20% SEABLOCK) at 1X^TM0.17 x phosphate buffer, 0.05% tween 20,6mM DTT), ligand affinity particles and test compound were subjected to binding reactions, all reactions were performed in 96-well plates with a final reaction volume of 0.135mL, incubated at room temperature with shaking for 1h, washing the affinity particles with washing buffer (1 x phosphate buffer, 0.05% tween 20), resuspended with elution buffer (1 x phosphate buffer, 0.05% tween 20,0.5 μ M non-biotinylated affinity ligand), incubated at room temperature with shaking for 30min, and the kinase concentration in the eluate was determined by qPCR. As used hereinThe kinase activity assay is described as KINOMEscan by Discovex corporation of Albrae St.Fremont, CA 94538, USA^TMDepartment, perform the assay.

Experiments show that the compound has obvious inhibitory activity on TYK2 in a kinase test.

Example D cell Activity assay

The utility of the disclosed compounds as TYK2 inhibitors can be evaluated by the following experiments.

Effect of TYK2 inhibitors on IFN- α induced expression of P-STAT3 in PBMCs

Whole blood from healthy subjects was collected, anticoagulated with heparin sodium, and PBMC (human peripheral blood mononuclear cells) were extracted. PBMCs were seeded at 1 × 106/well density in 96-well culture plates. The positive drug BMS986165 is diluted by 10 times with 1000nM as initial concentration and diluted by 8 concentrations with 3 times; the remaining test compounds were at 333 nM. DMSO with the same volume as the compound is added into the positive hole and the negative hole respectively, and the final concentration of the DMSO is 0.5%. After the compound was added, the cells were incubated at 37 ℃ for 1h, IFN-. alpha.was added to a final concentration of 5000U/mL for stimulation, and an equal volume of medium was added to the negative wells and incubated for 15 min. Centrifuging the cells to remove supernatant, lysing the cells, measuring P-STAT3 according to the ELISA kit instructions, reading absorbance at 450nm, and calculating IC₅₀Value or inhibition rate.

Inhibition of TF-1 cell proliferation by TYK2 inhibitor

TF-1 cells are inoculated in a 96-well culture plate at 20000/well density, each well is 80 mu L, blank wells are equal in amount of complete culture medium, 10 mu L of compound diluent is added into the 96-well plate B1-11, C1-11, E1-11 and F1-11, equal volume of 5% DMSO culture medium of the compound is added into positive wells and negative wells, and the final concentration of DMSO is 0.5%. After 30min, line B, C, D was added with GM-CSF (positive well) at a final concentration of 2ng/mL, and the remaining wells (line E, F, G) were added with an equal volume of medium to the cytokine (negative well). Incubating at 37 deg.C with 5% CO2 for 44 hr, adding Amania blue, incubating for 4 hr, detecting fluorescence intensity of each well at 540nM and 580nM wavelength, and calculating IC₅₀The value is obtained.

Inhibition of CTLL-2 cell proliferation by TYK2 inhibitors

CTLL-2 cells were plated at 20000/well density in 96-well plates at 90. mu.L per well, with equal volume of complete medium in blank wells. 10ul of different compound dilutions were added to each row of BC, DE, FG, and 5% DMSO media with equal volume of compound was added to the positive and negative wells, with final DMSO concentration at 0.5%. Incubating at 37 deg.C for 20 hr, adding Amanian blue, incubating for 4 hr, detecting fluorescence intensity of each well at 540nM and 580nM wavelength, and calculating IC₅₀The value is obtained.

According to experimental results, the compound disclosed by the invention has a good selective inhibition effect on TYK 2.

Finally, it should be noted that there are other ways of implementing the invention. Accordingly, the embodiments of the present invention will be described by way of illustration, but not limitation, of the invention as described. It should be understood that the above-described embodiments are exemplary and should not be construed as limiting the present invention, and those skilled in the art may make variations, modifications, substitutions and alterations to the above-described embodiments within the scope of the present invention. Modifications within the scope of the invention or equivalents added to the claims are also possible. All publications or patents cited herein are incorporated by reference.

Claims

1. A compound of formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof,

wherein:

x is N or CR^a(ii) a Y is N or CR^b(ii) a Z is N or CR^c；

R¹is-NH₂、C_1-6Alkyl radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C_6-10Aryl or 5-12 atoms of a heteroaryl group, wherein said-NH group₂、C_1-6Alkyl radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C_6-10Aryl and 5-12 atoms consisting of heteroaryl can be independently optionally substituted by 1,2,3,4 or 5 atoms selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by the radical hydroxyalkoxy;

each R⁶And R⁷Independently H, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-O-, heterocyclic radical of 3-8 atoms, C_6-10Aryl or heteroaryl of 5-10 atoms, wherein-OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-O-, heterocyclic radical of 3-8 atoms, C_6-10Aryl and heteroaryl of 5 to 10 atoms may be independently optionally substituted by 1,2,3,4 or 5R^xSubstituted by a group;

Each R⁹And R¹⁰Independently H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy or C_3-6Cycloalkyl, wherein said-OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy and C_3-6The cycloalkyl groups can be independently and optionally substituted by 1,2,3,4 or 5 groups selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted with a group of hydroxyalkoxy;

or R⁹、R¹⁰Together with the carbon atom to which they are attached form C_3-6Cycloalkyl or heterocyclyl consisting of 3 to 6 atoms, wherein said C is_3-6Cycloalkyl and heterocyclyl consisting of 3 to 6 atoms may be independently optionally substituted by 1,2,3,4 or 5 atoms selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Oxo, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by a group of hydroxyalkoxy;

R¹¹is H, D, C_1-6Alkyl radical, C_1-6Haloalkyl or C_3-6Cycloalkyl, wherein said C_1-6Alkyl radical, C_1-6Haloalkyl and C_3-6The cycloalkyl groups can be independently and optionally substituted by 1,2,3,4 or 5 groups selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Oxo, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_1-3Hydroxyalkoxy and C_3-6Cycloalkyl groups are substituted by the radicals;

each n is independently 0,1 or 2.

2. A compound according to claim 1, R¹is-NH₂、C_1-4Alkyl radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms, wherein the-NH group₂、C_1-4Alkyl radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl and 5-10 atoms consisting of heteroaryl can be independently optionally substituted by 1,2,3,4 or 5 atoms selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by the radical hydroxyalkoxy;

each R⁶And R⁷Independently H, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-O-, heterocyclic radical of 3-6 atoms, C_6-10Aryl or heteroaryl of 5-10 atoms, wherein-OH, -NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-O-, heterocyclic radical of 3-6 atoms, C_6-10Aryl and heteroaryl of 5 to 10 atoms may be independently optionally substituted by 1,2,3,4 or 5R^xSubstituted by a group.

3. A compound according to claim 1 or 2, R¹is-NH₂Methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, N-ethylpropyl-2-amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the group-NH-is a substituent selected from the group consisting of a carboxyl group, a salt₂Methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino, N-ethylpropyl-2-amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthalenylThe group, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl may be independently optionally substituted by 1,2,3,4 or 5 groups selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH is substituted by a group;

each R⁶And R⁷Independently H, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-alkynbutyl, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-O-, cyclobutyl-O-, cyclopentyl-O-, cyclohexyl-O-, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, and the like, Thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein said-OH, -NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-alkynbutyl, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-O-, cyclobutyl-O-, cyclopentyl-O-, cyclohexyl-O-, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, and the like, Thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl may be independently optionally substituted with 1,2,3,4 or 5R^xSubstituted by a group.

4. The compound of claim 1, each R⁹And R¹⁰Independently H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein-OH, -NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl may independently optionally be substituted by 1,2,3,4 or 5 substituents selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH is substituted by a group;

or R⁹、R¹⁰And the carbon atom to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl groups are each independently unsubstituted or substituted with 1,2,3,4 or 5 substituents independently selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Oxo, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH is substituted by a group;

R¹¹h, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are each independently unsubstituted or substituted by 1,2,3,4 or 5 substituents independently selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Oxo, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH、-OCH₂CH₂OH, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

5. The compound of claim 1, each R^a、R^bAnd R^cIndependently H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5-10 atoms, wherein-OH, -NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl and 5-10 atoms consisting of heteroaryl can be independently optionally substituted by 1,2,3,4 or 5 atoms selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by the radical hydroxyalkoxy;

each R^xIndependently F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy or C_3-6Cycloalkyl, wherein said-OH, -NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy and C_3-6The cycloalkyl groups can be independently and optionally substituted by 1,2,3,4 or 5 groups selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

6. A compound according to claim 1 or 5, each R^a、R^bAnd R^cIndependently H, D, F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-alkynbutyl, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein, the-OH and-NH are shown.₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-alkynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazoleThe group, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl may be independently optionally substituted by 1,2,3,4 or 5 groups selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH is substituted by a group;

each R^xIndependently F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-propargyl, 2-propargyl, 3-propargyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein-OH, -NH, -OH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH₂F、-CH₂Cl、-CHF₂、-CHCl₂、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CHF₂、-CH₂CHCl₂、-CHFCH₂F、-CHClCH₂Cl、-CH₂CF₃、-CH(CF₃)₂、-CF₂CH₂CH₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-propargyl, 2-propargyl, 3-propargyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups may independently optionally be substituted by 1,2,3,4 or 5 substituents selected from F, Cl, Br, I, -NO₂、CN、-OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

7. The compound of claim 1, which is a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof having one of the following structures:

8. a pharmaceutical composition comprising a compound of any one of claims 1-7, further comprising at least one of a pharmaceutically acceptable adjuvant, excipient, carrier, vehicle.

9. The pharmaceutical composition of claim 8, further comprising an additional therapeutic agent selected from a corticosteroid, rolipram, caftarin, a cytokine inhibitory anti-inflammatory drug, interleukin-10, a glucocorticoid, a salicylate, a nuclear translocation inhibitor, a steroid antiviral, an antiproliferative agent, an antimalarial, a TNF-a inhibitor, or a combination thereof.

10. Use of a compound of any one of claims 1-7 or a pharmaceutical composition of any one of claims 8-9 in the manufacture of a medicament for preventing, managing, treating or ameliorating a TYK2 mediated disease;

wherein said TYK 2-mediated disease is pancreatitis, asthma, allergy, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, discoid lupus erythematosus, scleroderma, chronic thyroiditis, Gray's disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory response, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Nett's syndrome, gout, traumatic arthritis, rheumatoid arthritis, Acute synovitis, pancreatic beta cell disease, a disease characterized by massive neutrophil infiltration, rheumatoid spondylitis, gouty arthritis, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, allograft rejection, fever due to infection, myalgia due to infection, cachexia secondary to infection, keloid formation, scar tissue formation, fever, influenza, osteoporosis, osteoarthritis, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, Shigella disease, Alzheimer's disease, Parkinson's disease, cerebral ischemia or neurodegenerative disease caused by traumatic injury, angiogenic disorders, viral diseases, CMV retinitis, AIDS, ARC, inflammatory bowel disease (EMC), inflammatory bowel disease, stroke, herpes, stroke, myocardial ischemia, ischemia in a stroke heart attack, organ hypoxia, vascular hyperplasia, cardiac reperfusion injury, renal reperfusion injury, thrombosis, cardiac hypertrophy, coagulation-induced enzymatic platelet aggregation, endotoxemia, toxic shock syndrome, prostaglandin endoperoxidase synthase-2 associated disease state, or pemphigus vulgaris.