阅读说明：本技术 哒嗪-3-甲酰胺类化合物、其制备方法及其在医药学上的应用 (Pyridazine-3-formamide compound, preparation method and application thereof in medicine and pharmacology ) 是由 陈向阳 庞育成 于 2018-08-07 设计创作，主要内容包括：本发明涉及适用于抑制或调控Janus激酶(JAK)、尤其是酪氨酸激酶2(TYK2)的哒嗪-3-甲酰胺类化合物、其制备方法及其在医药学上的应用。具体而言,本发明涉及一种通式(I)所示的化合物及其可药用的盐、含有所述化合物或其可药用的盐的药物组合物、应用所述化合物或其可药用的盐治疗和/或预防由Janus激酶介导的相关性病症、特别是自身免疫性疾病、炎性疾病和癌症的方法以及所述化合物或其可药用的盐的制备方法。其中通式(I)的各取代基与说明书中的定义相同。<Image he="513" wi="646" file="DDA0001757095890000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to pyridazine-3-formamide compounds suitable for inhibiting or regulating Janus kinases (JAK), in particular tyrosine kinase 2(TYK2), a preparation method and application thereof in medicine and pharmacology. Specifically, the invention relates to a compound shown in a general formula (I) and a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt thereof, a method for treating and/or preventing related diseases mediated by Janus kinases, particularly autoimmune diseases, inflammatory diseases and cancers by applying the compound or the pharmaceutically acceptable salt thereof, and a preparation method of the compound or the pharmaceutically acceptable salt thereof. Wherein each substituent group in the general formula (I) is defined as the specification.)

1. A compound of the general formula (I):

or pharmaceutically acceptable salts, prodrugs, stable isotopic derivatives, isomers and mixtures thereof, wherein:

z is N or CR¹；

Ring A is optionally substituted C_6-10An aromatic ring or a 5-10 membered heteroaromatic ring, wherein C is_6-10The aromatic ring being optionally substituted by C_3-7Fused with cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl;

l is a bond or optionally substituted C_1-6Alkylene, wherein one or two of said alkylene are non-adjacent-CH not linked to R₂-is optionally selected from-N (R)²)-、-N(R²)C(O)-、-C(O)N(R²)-、-N(R²)S(O)₂-、-S(O)₂N(R²) -, -O-, -C (O) -, -OC (O) -, -C (O) O-, -S-and-S (O)_m-is replaced by a group of;

r is selected from H, halogen, cyano, -SF₅、-OR³、-SR³、-NR³R⁴、-S(O)_mR³、-S(O)₂NR³R⁴、-C(O)R³、-C(O)OR³、-C(O)NR³R⁴、-C(O)N(R³)OR⁴、-OC(O)R³、-OC(O)NR³R⁴、-N(R³)C(O)OR⁴、-N(R³)C(O)R⁴、-N(R²)C(O)NR³R⁴、-C(O)N(R³)S(O)₂R⁴、-N(R³)S(O)₂R⁴Or optionally substituted C_3-7Cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;

R^a、R^b、R^c、R^dand R^eEach independently selected from H, halogen, cyano, -SF₅、-OR³、-S(O)_mR³、-S(O)₂NR³R⁴、-C(O)NR³R⁴Or optionally substituted C_1-6Alkyl radical, C_3-7Cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;

R¹selected from H, halogen, cyano or optionally substituted C_1-6An alkyl group;

R²、R³and R⁴Each independently selected from H or optionally substituted C_1-6Alkyl radical, C_3-7Cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or, R on the same nitrogen atom³And R⁴Optionally taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclic ring optionally containing additional heteroatoms, said heterocyclic ring being optionally substituted; and is

m is 1 or 2.

2. The compound according to claim 1, or pharmaceutically acceptable salts, prodrugs, stable isotopic derivatives, isomers and mixtures thereof, wherein Z is CH.

3. The compound according to claim 1 or 2, or pharmaceutically acceptable salts, prodrugs, stable isotopic derivatives, isomers and mixtures thereof, which is a compound of the following general formula (II):

wherein:

ring A is optionally substituted by one or more groups selected from halogen, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, -C (O) OR³、-OC_1-4Alkyl, -OC_1-4Haloalkyl and-SO₂C_1-4c substituted by alkyl substituents_6-10An aromatic ring or a 5-10 membered heteroaromatic ring, wherein C is_6-10The aromatic ring being optionally substituted by C_3-7Cycloalkyl or fused 4-7 membered heterocyclyl;

l is a bond or optionally substituted C_1-6Alkylene, wherein one or two of said alkylene are non-adjacent-CH not linked to R₂-is optionally selected from-N (R)²) -, -O-and-C (O) -;

r is selected from H, halogen, cyano, -SF₅、-OR³、-NR³R⁴、-S(O)₂R³、-S(O)R³、-S(O)₂NR³R⁴、-C(O)OR³、-C(O)R³、-C(O)NR³R⁴、-N(R³)C(O)OR⁴、-N(R³)C(O)R⁴、-C(O)N(R³)S(O)₂R⁴Or optionally substituted C_3-7Cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;

R^aand R^eEach independently selected from halogen;

R²is selected from H or C_1-6An alkyl group;

R³and R⁴Each independently selected from H or optionally substituted C_1-6Alkyl radical, C_3-7Cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or, R on the same nitrogen atom³And R⁴Optionally together with the nitrogen atom to which they are attached, form a 4-7 membered heterocyclic ring optionally containing additional heteroatoms, said heterocyclic ring being optionally substituted.

4. The compound according to any one of the preceding claims, or pharmaceutically acceptable salts, prodrugs, stable isotopic derivatives, isomers and mixtures thereof, wherein:

ring A is optionally substituted by one or two groups selected from halogen, cyano, C_1-4Alkyl, -C (O) OH, -OC_1-4Alkyl and-SO₂C_1-4C substituted by alkyl substituents_6-10An aromatic ring or a 5-10 membered heteroaromatic ring, wherein C is_6-10Aryl ring optionally and optionally selected from oxo and C_1-4A 4-7 membered heterocyclyl fused with a substituent for alkyl;

l is a bond or C_1-6Alkylene or-O-C_1-4An alkylene group;

r is selected from H, cyano, -SF₅、-OR³、-S(O)₂R³、-S(O)R³、-S(O)₂NR³R⁴、-C(O)OR³、-C(O)R³、-C(O)NR³R⁴、-C(O)N(R³)S(O)₂R⁴Optionally selected from-OH, C_1-4Alkyl, oxo, -O-C_1-4Alkyl radical, C_3-6C substituted by substituents of cycloalkyl and 4-6-membered heterocyclyl_3-7Cycloalkyl or 4-7 membered heterocyclyl, or optionally substituted by a group selected from-OH, C_1-4Alkyl, -O-C_1-4Alkyl radical, C_3-6Phenyl or 5-6 membered heteroaryl substituted with substituents of cycloalkyl and 4-6 membered heterocyclyl;

R^aand R^eEach independently selected from halogen;

R³and R⁴Each independently selected from H, C optionally substituted by halogen or-OH_1-6Alkyl, optionally selected from halogen, -OH, oxo and C_1-4C substituted by alkyl substituents_3-7Cycloalkyl or 4-7 membered heterocyclyl, or optionally substituted by a group selected from halogen, -OH and C_1-4Phenyl or 5-6 membered heteroaryl substituted with a substituent of alkyl; or, R on the same nitrogen atom³And R⁴Optionally together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring optionally containing additional heteroatoms, said heterocyclic ring optionally being selected from-OH, C_1-4Alkyl, -O-C_1-4Alkyl, oxo, C_3-6Cycloalkyl and 4-6 membered heterocyclyl.

5. The compound according to any one of the preceding claims, or pharmaceutically acceptable salts, prodrugs, stable isotopic derivatives, isomers and mixtures thereof, wherein:

ring A is optionally substituted by one or two groups selected from halogen, C_1-4Alkyl, -COOH, -OC_1-4Alkyl and-SO₂C_1-4A phenyl ring or a 5-6 membered heteroaromatic ring substituted with a substituent selected from the group consisting of oxo and C_1-4A 4-7 membered heterocyclyl fused with a substituent for alkyl;

l is a bond or C_1-6Alkylene or-O-C_1-4An alkylene group;

r is independently selected from H, cyano, -SF₅、-OR³、-S(O)₂C_1-6Alkyl, -S (O) C_1-6Alkyl, -S (O)₂NR³R⁴、-C(O)OH、-C(O)NR³R⁴、-C(O)NHS(O)₂C_1-6Alkyl, optionally selected from-OH, C_1-4Alkyl, oxo, -O-C_1-4Alkyl radical, C_3-64-7 membered heterocyclyl substituted with substituents of cycloalkyl and 4-6 membered heterocyclyl, or optionally substituted with C_1-4An alkyl-substituted 5-6 membered heteroaryl;

R^aand R^eEach independently selected from halogen;

R³and R⁴Each independently selected from H, C optionally substituted by halogen or-OH_1-6Alkyl, C optionally substituted by-OH_3-7Cycloalkyl, or optionally oxo or C_1-4An alkyl-substituted 4-7 membered heterocyclyl; or, R on the same nitrogen atom³And R⁴Optionally taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclic ring optionally containing an additional heteroatom selected from N, O and S, said heterocyclic ring optionally being selected from-OH, C_1-4Alkyl, -O-C_1-4Alkyl, oxo, C_3-6Cycloalkyl and 4-6 membered heterocyclyl.

6. The compound according to any one of the preceding claims, or pharmaceutically acceptable salts, prodrugs, stable isotopic derivatives, isomers and mixtures thereof, wherein ring a is optionally substituted with one or two selected from halogen, C_1-4Alkyl, -COOH, -OC_1-4Alkyl and-SO₂C_1-4Phenyl, pyridyl, pyridone, pyrimidine, indoline, isoindoline, 1-oxoisoindoline or pyrazole ring substituted with alkyl substituentPreferably, a benzene ring or a pyridine ring.

7. The compound according to any one of the preceding claims 1 to 5, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof, which is a compound of the following general formula (IIIa) or (IIIb):

wherein:

X¹、X²and X³Each independently selected from N or CG¹Provided that X is¹、X²And X³No more than two of N;

G¹selected from H, halogen, C_1-4Alkyl, -COOH, -OC_1-4Alkyl or-SO₂C_1-4An alkyl group;

L、R、R^aand R^eAs defined in the preceding claims.

8. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, prodrug, stable isotopic derivative, isomer and mixture thereof, selected from the group consisting of:

9. a pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture forms thereof and a pharmaceutically acceptable carrier and excipient.

10. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof or a pharmaceutical composition according to claim 9 for the manufacture of a medicament for the treatment and/or prevention of TYK2 mediated disorders of relevance selected from autoimmune diseases, inflammatory diseases, cancer, skin diseases, diabetes, ocular diseases, neurodegenerative diseases, allergic reactions, asthma and other obstructive airways diseases, transplant rejection.

Technical Field

The invention relates to a novel pyridazine-3-carboxamide compound or pharmaceutically acceptable salt thereof for regulating or inhibiting the activity of Janus kinases (JAK), especially tyrosine kinase 2(TYK2), a pharmaceutical composition containing the compound or pharmaceutically acceptable salt thereof, a preparation method of the compound or pharmaceutically acceptable salt thereof, and application of the compound or pharmaceutically acceptable salt thereof or pharmaceutical composition containing the compound or pharmaceutically acceptable salt thereof in preparing medicaments for treating and/or preventing related diseases mediated by the kinases, especially autoimmune diseases, inflammatory diseases and cancers and a using method thereof.

Background

Janus kinase (JAK) is a non-receptor tyrosine protein kinase consisting of four family members, i.e., JAK1, JAK2, JAK3, and TYK 2. JAK has 7 Homology domains in structure (JH), where JH1 Domain is a kinase region, JH2 Domain is a pseudo-kinase region (which modulates the activity of JH 1), and JH6 and JH7 are receptor binding regions. When the cell surface region of the Cytokine Receptor (Cytokine Receptor) binds to the Cytokine (Cytokine), JAKs associated with its intracellular region are phosphorylated, thereby creating a docking site for Signal Transducer and Activator of Transcription (STAT) proteins. STAT proteins are further phosphorylated by activated JAK, form dimers, enter the nucleus, regulate expression and transcription of related genes, and effect transduction of signals from the cell membrane to the nucleus (Lionard et al, Ann. Rev. Immunol.1998, 16, 293-). Therefore, JAKs transduce cytokine-mediated signals through the JAK-STAT pathway, playing an important role in many cellular functions such as cytokine-dependent regulated cell proliferation, differentiation, apoptosis, and immune response, and are one of the hot Targets for the treatment of inflammatory diseases, autoimmune diseases, and cancer (Alicea-velazqueet. al, curr. drug Targets 2011, 12, 546-55). The pan-JAK inhibitor Tofacitinib (Tofacitinib) from pficine was approved for the treatment of rheumatoid arthritis in 2012; the JAK1/JAK2 inhibitor Ruxolitinib (Ruxolitinib), developed by the american company inc, was approved for the treatment of myelofibrosis in 2011.

Gene knockout studies have shown that JAKs and STATs play a highly specific role in the control of different immune responses. One JAK kinase can participate in the signal transduction process of various cytokines, the signal path of one cytokine can also activate a plurality of JAK kinases, but the cytokine has certain selectivity on activated STAT protein, such as Interleukin (IL) -4 activated STAT6, IL-12 but specifically activated STAT 4. JAK1, JAK2, TYK2 are widely present in various tissues and cells, and JAK1 is closely related to activation of inflammatory factors such as IL-6 and Interferon (IFN), so that a JAK1 selective inhibitor is considered to have a potential therapeutic effect on autoimmune diseases such as Rheumatoid Arthritis (RA) and psoriasis; JAK2 can independently mediate cytokines such as Erythropoietin (EPO) and Thrombopoietin (TPO) (Won et al, BMC Bioinformatics2009, 10, S53), and is closely related to proliferation and differentiation of blood cells. JAK3 is only present in bone marrow and lymphatic system, mediates the signal transduction of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, and these cytokines have important roles in inducing the proliferation and differentiation of T cells, activating B cells to produce antibodies, activating macrophages, enhancing the activity of natural killer cells (NK cells), and inducing other cytokines such as IFN. Therefore, the JAK3 selective inhibitor is expected to have an important effect on treatment of organ transplantation, autoimmune diseases, inflammatory pneumonia and the like.

The JAK/STAT pathway can be overactivated by autocrine and paracrine cytokines, as well as by several mutations, and is associated with a variety of malignancies, such as breast, liver, prostate, colon, lung, pancreatic, bladder, and diffuse large B-cell lymphoma, among others (Tan et al, curr. drug Targets 2014, 15, 1341-53; Lam et al, Blood 2008, 111, 3701-13). The mutant JAK2/V617F of JAK2 occurs in the pseudo-JH 2 pseudo-kinase region, causing JAK2 conformational changes that result in sustained activation of the JH1 kinase region independent of extracellular cytokine signals, which in turn causes cell proliferation and hematologic cancer, closely related to Polycythemia Vera (PV), essential thrombocythemia (essential thrombocythemia) and Myelofibrosis (Myelofibrosis, MF) (O' Shea et al, ann.rev.med.2015, 66, 311-28). The JAK2 inhibitor Ruxolitinib (Ruxolitinib) can be used for treating the blood diseases, but the curative effect is unrelated to the existence of JAK2/V617F mutation, and the result shows that the antitumor activity is not based on the inhibition of the signal transmission involved in JAK2/V617F but also from the regulation and control of JAK 1-STAT.

TYK2 is involved in signal transduction of inflammatory cytokines such as Interferons (IFNs), IL-12 and IL-23, etc., and plays a key role in innate and adaptive immunity TYK2 knockdown mice have normal red blood cell numbers and are capable of surviving, but JAK3 deficient mice are severely immunodeficient, and JAK1 or 685JAK 2 knockout mice are embryonically lethal, but in humans, no JAK1/2 loss-related disease is found, perhaps indirectly indicating the importance of the physiological function of JAK 1/2. 1 patient with a null mutation in the TYK2 gene has hyper-immunoglobulin E syndrome, but seven other null mutations in TYK2 homotypic binding do not have hyper-immunoglobulin E syndrome, but rather, inhibition of TYK2 does not cause lack of acute toxicity of TYK2 expression, as a result of attenuated signaling of IL-12 and INF α/β responses increase of mycobacterial or viral infections, thus inhibition of TYK2 does not cause a lack of acute toxicity of the expression of TYK2, which is reflected in the attenuated signal transmission of various proinflammatory cytokines and sensitivity of TYK receptor targeting of systemic autoimmune diseases such as a clinically relevant systemic autoimmune psoriasis, also has been shown by a further evidence of systemic autoimmune receptor targeting of systemic autoimmune psoriasis, such as systemic autoimmune psoriasis 9634.

TYK2 is also associated with some cancers, such as abnormal survival of acute lymphocytic leukemia (T-ALL) cells associated with activation of TYK 2. Knockout experiments showed that 88% of T-ALL cell lines and 63% of T-ALL cells from patients were TYK2 dependent, and thus TYK2 was an oncogene of T-ALL (Sanda et al, Cancer Disc.2013, 3, 564-77). The TYK2 selective inhibitor NDI-031301 can induce apoptosis to inhibit the growth of human T-ALL cell lines, has good safety and curative effect on a mouse model with KOPT-K1T-ALL tumor cells (Akahane et al, British J.Haematol.2017, 177, 271-82), and shows the prospect of the TYK2 selective inhibitor in the aspect of treating T-ALL.

At present, several inhibitor drugs aiming at JAK1/2/3, such as Tofacitinib (Tofacitinib), Baricitinib (Baricitinib) and Ruxolitinib (Ruxolitinib), and also a plurality of clinically tested drugs, such as Upatinib (Uptacetitinib), Filgotinib, Peicitinib and the like, exist in the market, but only one TYK2 specific inhibitor BMS-986165 is reported to enter clinical tests. Because different immune responses are regulated by JAK in JAK-STAT, selective inhibitors of different JAK kinases have different potential uses and toxic and side effects. Ruxolitinib (Ruxolitinib) is used for treating myelofibrosis, has good safety and has no toxic or side effect on non-target organs. However, Tofacitinib (Tofacitinib) has certain toxic and side effects because of its activity of inhibiting JAK2, and influences the generation of blood cells and lymphocytes, and limits the clinical dosage of the medicine in RA. Therefore, the development of TYK2 specific inhibitors which are more selective than JAK2, thereby avoiding anemia side effects caused by inhibiting the activity of JAK2 (Vincenti et al, am. J. Transplant.2012, 12, 2446-56; Ghoreschi et al, Nature Immunol.2009, 4, 356-. However, due to the high sequence similarity of the active sites of the JAK kinase family, it is quite difficult to develop a highly selective TYK2 inhibitor. Although some patent applications for selective inhibitors of TYK2 have been disclosed so far, including WO2010142752, WO2012062704, WO2013180265, WO2015032423, WO2015131080 and WO2017040757, etc., based on the promise exhibited by TYK2 specific inhibitors in the treatment of inflammatory diseases, autoimmune diseases, cancer, etc., there is still a need to develop new compounds with better druggability, stronger drug efficacy and higher TYK2 kinase selectivity. Through continuous efforts, the present inventors designed compounds having a structure represented by general formula (I), and found that compounds having such a structure exhibit excellent effects and actions.

Disclosure of Invention

The invention provides a compound shown in a general formula (I), a prodrug, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer and a mixture form thereof, which are used as Janus kinase, especially TYK2 inhibitors:

wherein:

z is N or CR¹；

Ring A is optionally substituted C_6-10An aromatic ring or a 5-10 membered heteroaromatic ring, wherein C is_6-10The aromatic ring being optionally substituted by C_3-7Cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl ring fused;

l is a bondOr optionally substituted C_1-6Alkylene, wherein one or two of said alkylene are non-adjacent-CH not linked to R₂-is optionally selected from-N (R)²)-、-N(R²)C(O)-、-C(O)N(R²)-、-N(R²)S(O)₂-、-S(O)₂N(R²) -, -O-, -C (O) -, -OC (O) -, -C (O) O-, -S-and-S (O)_m-is replaced by a group of;

r is selected from H, halogen, cyano, -SF₅、-OR³、-SR³、-NR³R⁴、-S(O)_mR³、-S(O)₂NR³R⁴、-C(O)R³、-C(O)OR³、-C(O)NR³R⁴、-C(O)N(R³)OR⁴、-OC(O)R³、-OC(O)NR³R⁴、-N(R³)C(O)OR⁴、-N(R³)C(O)R⁴、-N(R²)C(O)NR³R⁴、-C(O)N(R³)S(O)₂R⁴、-N(R³)S(O)₂R⁴Or optionally substituted C_3-7Cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;

R^a、R^b、R^c、R^dand R^eEach independently selected from H, halogen, cyano, -SF₅、-OR³、-S(O)_mR³、-S(O)₂NR³R⁴、-C(O)NR³R⁴Or optionally substituted C_1-6Alkyl radical, C_3-7Cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;

R¹selected from H, halogen, cyano or optionally substituted C_1-6An alkyl group;

R²、R³and R⁴Each independently selected from H or optionally substituted C_1-6Alkyl radical, C_3-7Cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or, R on the same nitrogen atom³And R⁴Optionally taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclic ring optionally containing additional heteroatoms; said heterocycle being optionally substituted;

and m is 1 or 2.

The invention further relates to a pharmaceutical composition which comprises the compound shown in the general formula (I) or pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers and mixtures thereof, and pharmaceutically acceptable carriers and excipients.

Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixtures thereof, or the pharmaceutical composition, for the manufacture of a medicament for the treatment or prevention of TYK2 mediated diseases including, but not limited to, autoimmune diseases, inflammatory diseases including intestinal inflammation, cancer, skin diseases, diabetes, ocular diseases, neurodegenerative diseases, allergic reactions, asthma and other obstructive airways diseases, transplant rejection and the like.

In a further aspect of the present invention there is provided a method of treating or preventing TYK2 mediated diseases, including but not limited to autoimmune diseases, inflammatory diseases including intestinal inflammation, cancer, skin diseases, diabetes, ocular diseases, neurodegenerative diseases, allergic reactions, asthma and other obstructive airways diseases, transplant rejection and the like, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixtures thereof, or a pharmaceutical composition comprising the compound.

Yet another aspect of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, prodrugs, stable isotopic derivatives, isomers and mixtures thereof, for use in the treatment or prevention of TYK 2-mediated diseases including, but not limited to, autoimmune diseases, inflammatory diseases including intestinal inflammation, tumors, skin diseases, diabetes, ocular diseases, neurodegenerative diseases, allergic reactions, asthma and other obstructive airways diseases, transplant rejection and the like.

Detailed Description

Definition of

Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

As used herein, the expression "C_x-y"denotes a range of carbon atom numbers wherein x and y are both integers, e.g. C_3-8Cycloalkyl denotes cycloalkyl having 3 to 8 carbon atoms, i.e. cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms. It is also understood that "C" is_3-8"also includes any subrange therein, e.g. C_3-7、C_3-6、C_4-7、C_4-6、C_5-6And the like.

"alkyl" refers to a saturated straight or branched chain hydrocarbyl group containing 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, and the like. The alkyl group may be optionally substituted.

"alkylene" refers to a divalent group of a straight or branched chain saturated hydrocarbon containing 1 to 20 carbon atoms, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms. Non-limiting examples of alkylene groups include-CH₂-、-CH(CH₃)-、-CH₂CH₂-、-CH₂CH₂CH₂-、-(CH₃)C(CH₃)-、-CH₂CH₂CH₂CH₂-、-CH₂CH(CH₃)CH₂-and the like. The alkylene group may be optionally substituted.

"cycloalkyl" refers to a saturated cyclic hydrocarbyl substituent containing from 3 to 14 carbon ring atoms. Cycloalkyl groups may be monocyclic, typically containing 3 to 8, 3 to 7, or 3 to 6 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Cycloalkyl groups may alternatively be bi-or tricyclic fused together, such as decahydronaphthyl. The cycloalkyl group may be optionally substituted.

"Heterocyclyl or heterocycle" means a saturated or partially unsaturated monocyclic or polycyclic cyclic group comprising 3 to 20 ring atoms, which may be, for example, 3 to 14, 3 to 12, 3 to 10, 3 to 8, 3 to 6 or 5 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O)_m(wherein m is an integer of 0 to 2) excluding the ring moiety of-O-O-, -O-S-or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, more preferably 3 to 10 ring atoms, more preferably 4 to 7 ring atoms, more preferably 4 to 6 ring atoms, most preferably 5 or 6 ring atoms, of which 1 to 4 are heteroatoms, more preferably 1 to 3 are heteroatoms, most preferably 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, oxetanyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azetidinyl, and the like. Polycyclic heterocyclic groups include fused, bridged or spiro polycyclic heterocyclic groups, e.g. octahydrocyclopenta [ c ]]Pyrrole, octahydropyrrolo [1, 2-a ] s]Pyrazine, 3, 8-diazabicyclo [3.2.1]Octane, 5-azaspiro [2.4 ]]Heptane, 2-oxa-7-azaspiro [3.5]Nonane and the like. The heterocyclic group or heterocycle may be optionally substituted.

"aryl or aromatic ring" means an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 membered, such as phenyl and naphthyl, most preferably phenyl. The aryl ring may be fused to an optionally substituted heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:

and the like.

The aryl or aromatic ring may be optionally substituted.

"heteroaryl or heteroaromatic ring" refers to a heteroaromatic system comprising 5 to 14 ring atoms, wherein 1 to 4 ring atoms are selected from heteroatoms including oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably heteroaryl is 5 or 6 membered, for example furyl, thienyl, pyridyl, pyridonyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl and the like. The heteroaryl ring may be fused to an optionally substituted aryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:

and the like.

The heteroaryl or heteroaryl ring may be optionally substituted.

"halogen" means fluorine, chlorine, bromine or iodine.

"cyano" means-CN.

"oxo" means ═ O.

"carbonyl" refers to the group — C (═ O) -.

"Sulfonyl" means-S (O)₂-a group.

"sulfinyl" refers to the-S (O) -group.

"optional" means 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 expression includes the case where the heterocyclic group is substituted with an alkyl and the case where the heterocyclic group is not substituted with an alkyl.

"optionally substituted" means that one or more, preferably 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their placeChemical positions of energy, one skilled in the art can determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds. Such substituents include, but are not limited to, halogen, cyano, nitro, oxo, -SF₅、C_1-4Alkyl radical, C_3-7Cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -OR ', -NR' R ', -C (O) R', -C (O) OR ', -C (O) NR' R ', -C (O) N (R') OR ', -OC (O) R', -OC (O) NR 'R', -N (R ') C (O) OR', -N (R ') C (O) R', -N (R ') C (O) NR' R ', -N (R') S (O)₂R"、-S(O)_mR' (m is 1 or 2), -S (O)₂NR 'R' and the like, wherein the alkyl, cycloalkyl, heterocyclyl, phenyl or heteroaryl is optionally substituted with one or more substituents selected from halogen, cyano, C_1-4Alkyl radical, C_3-7Cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -OR ', -NR ' R ", -C (O) R ', -C (O) OR ', -C (O) NR ' R", -OC (O) NR ' R ", -N (R ') C (O) OR", -N (R ') C (O) R ", -N (R '") C (O) NR ' R ", -N (R ') S (O)₂R"、-S(O)₂R′、-S(O)₂NR 'R' is substituted; r ', R ' and R ' are each independently selected from H, C optionally containing a heteroatom selected from N, O and S_1-4Alkyl radical, C_3-7Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, phenyl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-4Alkyl, halo C_1-4Alkyl, -O-C_1-4Alkyl is substituted by a substituent; r 'and R' on the same nitrogen atom optionally form together with the nitrogen atom to which they are attached a 4-7 membered heterocyclic ring optionally containing an additional heteroatom selected from O, S and N.

"isomers" refer to compounds having the same molecular formula but differing in the nature or order of their atomic bonding or the spatial arrangement of their atoms. Isomers that differ in the arrangement of atoms in space are referred to as "stereoisomers". Stereoisomers include optical isomers, geometric isomers and conformational isomers.

The compounds of the present invention may exist in the form of optical isomers. Depending on the configuration of the substituents around the chiral carbon atom, these optical isomers are either in the "R" or "S" configuration. Optical isomers include enantiomers and diastereomers. Methods for preparing and separating optical isomers are known in the art.

Geometric isomers may also exist for the compounds of the present invention. The present invention contemplates various geometric isomers resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl groups or heterocyclic groups, and mixtures thereof. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as either the Z or E configuration, and substituents around cycloalkyl or heterocyclic rings are designated as either the cis or trans configuration.

The compounds of the invention may also exhibit tautomerism, such as keto-enol tautomerism.

It is to be understood that the present invention includes any tautomeric or stereoisomeric form and mixtures thereof, and is not to be limited solely to any one tautomeric or stereoisomeric form used in the nomenclature or chemical structural formulae of the compounds.

"isotopes" include all isotopes of atoms occurring in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as but not limited to²H(D)、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically-labeled reagent in place of a non-isotopically-labeled reagent. Such compounds have a variety of potential uses, for example as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds have the potential to favorably alter biological, pharmacological or pharmacokinetic properties.

The compounds of the present invention may be administered in the form of prodrugs. "prodrug" refers to a derivative that is converted to the biologically active compound of the present invention under physiological conditions in vivo, e.g., by oxidation, reduction, hydrolysis, etc. (each of which is carried out with or without the participation of an enzyme). Examples of prodrugs are the following compounds: wherein an amino group in a compound of the invention is acylated, alkylated or phosphorylated, e.g. eicosanoylamino, alanylamino, pivaloyloxymethylamino, or wherein a hydroxyl group is acylated, alkylated, phosphorylated or converted to a borate, e.g. acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaroyloxy, alanyloxy, or wherein a carboxyl group is esterified or amidated, or wherein a sulfhydryl group forms a disulfide bridge with a carrier molecule, e.g. a peptide, that selectively delivers a drug to a target and/or to the cytosol of a cell. These compounds can be prepared from the compounds of the present invention according to known methods.

"pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. Where the compounds of the invention contain one or more acidic or basic groups, the invention also includes their corresponding pharmaceutically acceptable salts. Thus, the compounds of the invention containing acidic groups can be present in the form of salts and can be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium, potassium, calcium, magnesium or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine or amino acids. The compounds of the invention containing basic groups can be present in the form of salts and can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compounds of the invention contain both acidic and basic groups in the molecule, the invention also includes inner salts or betaine salts in addition to the salt forms mentioned. The salts can be obtained by conventional methods known to the person skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants or by anion exchange or cation exchange with other salts.

"pharmaceutical composition" refers to a composition containing one or more of the compounds described herein, or pharmaceutically acceptable salts, prodrugs, stable isotopic derivatives, isomers, and mixtures thereof, as well as other components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

Thus, when reference is made herein to "a compound", "a compound of the invention" or "a compound of the invention", all such compound forms are included, for example, pharmaceutically acceptable salts, prodrugs, stable isotopic derivatives, isomers and mixtures thereof.

As used herein, the term "autoimmune or inflammatory disease" includes, but is not limited to, arthritis, Hashimoto's thyroiditis, autoimmune hemolytic anemia, pernicious anemic autoimmune atrophic gastritis, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves ' disease, primary biliary cirrhosis, hepatitis, primary sclerosing cholangitis, chronic invasive hepatitis, non-alcoholic steatohepatitis, ulcerative colitis, membranous glomerulopathy, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis, dermatomyositis, I-type interferon diseases including Aicardi-Gouti syndrome and other systemic sclerosis which overexpresses type I interferons, Mendelian disease, polyarteritis nodosa, multiple sclerosis, relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, bullous pemphigoid; in addition, autoimmune diseases based on O-cells (humoral) or T-cells, including Cogen syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, type I or juvenile diabetes, thyroiditis.

As used herein, the term "intestinal inflammation" includes, but is not limited to, Crohn's disease, ulcerative colitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis.

As used herein, the term "cancer/tumor" includes, but is not limited to, cancers of the digestive/gastrointestinal tract, colon, liver, skin (including mast cell and squamous cell), breast, ovary, prostate, lymphoma, leukemia (including acute myelogenous and chronic myelogenous leukemias), kidney, lung, muscle, bone, bladder, brain, melanoma (including oral and metastatic melanoma), kaposi's sarcoma (myeloma including multiple myeloma), myeloproliferative diseases, proliferative diabetic retinopathy, angiogenesis-related disorders/tumors.

Herein, the term "skin diseases" includes, but is not limited to, atopic dermatitis, eczema, psoriasis, scleroderma, pruritus or other symptoms of pruritus, vitiligo, alopecia.

As used herein, the term "diabetes" includes, but is not limited to, type I diabetes and diabetic complications.

As used herein, the term "ocular disease" includes, but is not limited to, keratoconjunctivitis, uveitis (including uveitis associated with Behcet's disease and uveitis caused by the lens), keratitis, herpetic keratitis, keratoconitis, corneal epithelial dystrophy, keratoleukopenia, epibulbar inflammation, Mooren's ulcer, scleritis, Graves ' ocular disease, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), small blisters, iridocyclitis, sarcoidosis, endocrine ocular disease, sympathetic ophthalmia, allergic conjunctivitis, ocular neovascularization.

Herein, the term "neurodegenerative disease" includes, but is not limited to, motor neuron disease, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, huntington's disease, cerebral ischemia; neurodegenerative diseases caused by trauma, injury, glutamate neurotoxicity or hypoxia; ischemia/reperfusion injury in stroke, myocardial ischemia, renal ischemia, heart attack, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia or platelet aggregation.

As used herein, the term "allergic response" includes, but is not limited to, allergic dermatitis (including equine allergic diseases such as hypersensitivity to biting), summer eczema, itching of hoofs, cramps, inflammatory airway diseases, repeated obstruction of the airway, airway hyperresponsiveness, chronic obstructive pulmonary disease in mammals.

As used herein, the term "asthma and other obstructive airways diseases" includes, but is not limited to, chronic or excessive asthma, delayed asthma, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dust asthma.

As used herein, the term "transplant rejection" includes, but is not limited to, islet transplant rejection, bone marrow transplant rejection, graft-versus-host disease, organ and cell transplant rejection (e.g., bone marrow, cartilage, cornea, heart, intervertebral disc, pancreatic islets, kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine, or trachea), xenotransplantation.

As used herein, the term "therapeutically effective amount" is meant to include an amount of a compound of the present invention that is effective to inhibit the function of TYK2 and/or to treat or prevent the disorder in question.

The term "patient" as used herein refers to a mammal, especially a human.

Compound (I)

One aspect of the present invention is a compound of formula (I), prodrugs, stable isotopic derivatives, pharmaceutically acceptable salts, isomers and mixtures thereof:

wherein:

z is N or CR¹；

Ring A is optionally substituted C_6-10An aromatic ring or a 5-10 membered heteroaromatic ring, wherein C is_6-10The aromatic ring being optionally substituted by C_3-7Fused with cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl;

l is a bond or optionally substituted C_1-6Alkylene, wherein one or two of said alkylene are non-adjacent-CH not linked to R₂-is optionally selected from-N (R)²)-、-N(R²)C(O)-、-C(O)N(R²)-、-N(R²)S(O)₂-、-S(O)₂N(R²) -, -O-, -C (O) -, -OC (O) -, -C (O) O-, -S-and-S (O)_m-is replaced by a group of;

r is selected from H, halogen, cyano, -SF₅、-OR³、-SR³、-NR³R⁴、-S(O)_mR³、-S(O)₂NR³R⁴、-C(O)R³、-C(O)OR³、-C(O)NR³R⁴、-C(O)N(R³)OR⁴、-OC(O)R³、-OC(O)NR³R⁴、-N(R³)C(O)OR⁴、-N(R³)C(O)R⁴、-N(R²)C(O)NR³R⁴、-C(O)N(R³)S(O)₂R⁴、-N(R³)S(O)₂R⁴Or optionally substituted C_3-7Cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;

R^a、R^b、R^c、R^dand R^eEach independently selected from H, halogen, cyano, -SF₅、-OR³、-S(O)_mR³、-S(O)₂NR³R⁴、-C(O)NR³R⁴Or optionally substituted C_1-6Alkyl radical, C_3-7Cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;

R¹selected from H, halogen, cyano or optionally substituted C_1-6An alkyl group;

R²、R³and R⁴Each independently selected from H or optionally substituted C_1-6Alkyl radical, C_3-7Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 memberedA heteroaryl group; or, R on the same nitrogen atom³And R⁴Optionally taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclic ring optionally containing additional heteroatoms, said heterocyclic ring being optionally substituted;

and m is 1 or 2.

In some embodiments, Z is CH.

In some embodiments, the compound of formula (I) has the following formula (II):

wherein:

ring A is optionally substituted by one or more groups selected from halogen, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, -C (O) OR³、-OC_1-4Alkyl, -OC_1-4Haloalkyl and-SO₂C_1-4C substituted by alkyl substituents_6-10An aromatic ring or a 5-10 membered heteroaromatic ring, wherein C is_6-10The aromatic ring being optionally substituted by C_3-7Cycloalkyl or fused 4-7 membered heterocyclyl;

l is a bond or optionally substituted C_1-6Alkylene, wherein one or two of said alkylene are non-adjacent-CH not linked to R₂-is optionally selected from-N (R)²) -, -O-and-C (O) -;

r is selected from H, halogen, cyano, -SF₅、-OR³、-NR³R⁴、-S(O)₂R³、-S(O)R³、-S(O)₂NR³R⁴、-C(O)OR³、-C(O)R³、-C(O)NR³R⁴、-N(R³)C(O)OR⁴、-N(R³)C(O)R⁴、-C(O)N(R³)S(O)₂R⁴Or optionally substituted C_3-7Cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;

R^aand R^eEach independently selected from halogen;

R²is selected from H or C_1-6An alkyl group;

R³and R⁴Each independently selected from H or optionally substituted C_1-6Alkyl radical, C_3-7Cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or, R on the same nitrogen atom³And R⁴Optionally together with the nitrogen atom to which they are attached, form a 4-7 membered heterocyclic ring optionally containing additional heteroatoms, said heterocyclic ring being optionally substituted.

In other embodiments, the compound is a compound of formula (II) above, or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, isomer, and mixture thereof, wherein:

ring A is optionally substituted by one or two groups selected from halogen, cyano, C_1-4Alkyl, -C (O) OH, -OC_1-4Alkyl and-SO₂C_1-4C substituted by alkyl substituents_6-10An aromatic ring or a 5-10 membered heteroaromatic ring, wherein C is_6-10Aryl ring optionally and optionally selected from oxo and C_1-4A 4-7 membered heterocyclyl fused with a substituent for alkyl;

l is a bond or C_1-6Alkylene or-O-C_1-4An alkylene group;

r is selected from H, cyano, -SF₅、-OR³、-S(O)₂R³、-S(O)R³、-S(O)₂NR³R⁴、-C(O)OR³、-C(O)R³、-C(O)NR³R⁴、-C(O)N(R³)S(O)₂R⁴Or optionally selected from-OH, C_1-4Alkyl, oxo, -O-C_1-4Alkyl radical, C_3-6C substituted by substituents of cycloalkyl and 4-6-membered heterocyclyl_3-7Cycloalkyl or 4-7 membered heterocyclyl, or optionally substituted by a group selected from-OH, C_1-4Alkyl, -O-C_1-4Alkyl radical, C_3-6Phenyl or 5-6 membered heteroaryl substituted with substituents of cycloalkyl and 4-6 membered heterocyclyl;

R^aand R^eEach independently selected from halogen;

R³and R⁴Each independently selected from H, C optionally substituted by halogen or-OH_1-6Alkyl, optionally selected from halogen, -OH, oxo and C_1-4C substituted by alkyl substituents_3-7Cycloalkyl or 4-7 membered heterocyclyl, or optionally substituted by a group selected from halogen, -OH and C_1-4Phenyl or 5-6 membered heteroaryl substituted with a substituent of alkyl; or, R on the same nitrogen atom³And R⁴Optionally together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring optionally containing additional heteroatoms, said heterocyclic ring optionally being selected from-OH, C_1-4Alkyl, -O-C_1-4Alkyl, oxo, C_3-6Cycloalkyl or a 4-6 membered heterocyclyl.

In still other embodiments, the compound is a compound of formula (II) above, or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, isomer, and mixture thereof, wherein:

ring A is optionally substituted by one or two groups selected from halogen, C_1-4Alkyl, -COOH, -OC_1-4Alkyl and-SO₂C_1-4A phenyl ring or a 5-6 membered heteroaromatic ring substituted with a substituent selected from the group consisting of oxo and C_1-4A 4-7 membered heterocyclyl fused with a substituent for alkyl;

l is a bond or C_1-6Alkylene or-O-C_1-4An alkylene group;

r is independently selected from H, cyano, -SF₅、-OR³、-S(O)₂C_1-6Alkyl, -S (O) C_1-6Alkyl, -S (O)₂NR³R⁴、-C(O)OH、-C(0)NR³R⁴、-C(O)NHS(O)₂C_1-6Alkyl, optionally selected from-OH, C_1-4Alkyl, oxo, -O-C_1-4Alkyl radical, C_3-64-7 membered heterocyclyl substituted with substituents of cycloalkyl and 4-6 membered heterocyclyl, or optionally substituted with C_1-4An alkyl-substituted 5-6 membered heteroaryl;

R^aand R^eEach independently selected from halogen;

R³and R⁴Each independently selected from H, C optionally substituted by halogen or-OH_1-6Alkyl, C optionally substituted by-OH_3-7Cycloalkyl, or optionally oxo or C_1-4Alkyl substituted 4-7 membered heterocyclic group(ii) a Or, R on the same nitrogen atom³And R⁴Optionally taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclic ring optionally containing an additional heteroatom selected from N, O and S, said heterocyclic ring optionally being selected from-OH, C_1-4Alkyl, -O-C_1-4Alkyl, oxo, C_3-6Cycloalkyl and 4-6 membered heterocyclyl.

In some embodiments, ring a is optionally substituted with halo, cyano, C_1-4Alkyl, -C (O) OH, -OC_1-4Alkyl or-SO₂C_1-4Alkyl-substituted benzene, pyridine, pyridone, pyrimidine, indoline, isoindoline, 1-oxoisoindoline or pyrazole rings, preferably benzene and pyridine rings.

In some embodiments, ring a is an unsubstituted phenyl ring; in other embodiments, ring A is substituted with one or two groups selected from halogen, -C (O) OH, -OC_1-4Alkyl and-SO₂C_1-4A phenyl ring substituted with a substituent of an alkyl group; in still other embodiments, ring a is a phenyl ring substituted with one halogen, such as fluorine.

In some embodiments, ring a is optionally selected from oxo and C_1-4The 4-7 membered heterocyclic fused benzene ring substituted with a substituent for an alkyl group is, for example, an indoline ring, an isoindoline ring or a methyl-substituted 1-oxoisoindoline ring.

In some embodiments, ring a is an unsubstituted pyridine ring; in other embodiments, ring A is substituted with one or two groups selected from halogen and C_1-4A pyridine ring substituted with a substituent of an alkyl group; in other embodiments, ring A is C_1-4An alkyl-substituted pyridone ring. In some embodiments, the pyridine ring is attached to the parent nucleus, e.g., via the 2-position. In some embodiments, the pyridine ring is attached to the parent nucleus, e.g., via the 3-position.

In some embodiments, ring a is a substituted or unsubstituted pyrimidine ring. In a preferred embodiment, the pyrimidine ring is attached to the parent nucleus via the 2-position.

In some embodiments, ring a is an unsubstituted pyrazole ring or a pyrazole ring substituted with a methyl group. In some embodiments, the pyrazole ring is attached to the parent nucleus, e.g., via the 4-position. In some embodiments, the pyrazole ring is attached to the parent nucleus, e.g., via the 3-position.

In some embodiments, the "L-R" moiety is attached para to the-NH-group on ring A. In other embodiments, the "L-R" moiety is attached to ring A meta to the-NH-group.

Yet another aspect of the present invention is a compound represented by the above general formula (I) or (II) or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, isomer, and mixture form thereof, the compound having the general formula (IIIa) or (IIIb):

wherein:

X¹、X²and X³Each independently selected from N or CG¹Provided that X is¹、X²And X³No more than two of N;

G¹selected from H, halogen, C_1-4Alkyl, -COOH, -OC_1-4Alkyl or-SO₂C_1-4An alkyl group;

L、R、R^aand R^eAs defined above.

In some embodiments of the compounds of formula (IIIa), X¹、X²And X³Are both CH.

In some embodiments of the compounds of formula (IIIa), X¹、X²And X³No more than two of which are N.

In some embodiments of the compounds of formula (IIIa), X¹Is N and X²And X³Is CH.

In some embodiments of the compounds of formula (IIIa), X²Is N and X¹And X³Is CH.

In some embodiments of the compounds of formula (IIIa), X³Is N and X¹And X²Is CH.

In some embodiments of the compounds of formula (IIIa), X¹And X³Is N and X²Is CH.

In some embodiments of the compounds of formula (IIIa), X¹And X²Is N and X³Is CH.

In some embodiments of the compounds of formula (IIIa), X²And X³Is N and X¹Is CH.

In some embodiments of the compounds of formulae (I), (II), and (IIIa), L is a bond.

In some embodiments of the compounds of formula (I), (II) and (IIIa), L is C_1-6Alkylene radicals, e.g. CH₂-or- (CH)₃)C(CH₃)-。

In some embodiments of the compounds of formulae (I), (II), and (IIIa), L is-O-C_1-4Alkylene radicals, e.g. O-CH₂-。

In some embodiments of the compounds of formula (I), (II) and (IIIa), L is a bond and R is-OC_1-6Alkyl or-OC_1-6Haloalkyl radicals, e.g. -OCH₃、-OC₂H₅、-OCHF₂。

In some embodiments of the compounds of formulae (I), (II), and (IIIa), L is a bond, R is-S (O)₂C_1-6Alkyl or-S (O) C_1-6Alkyl radicals, e.g., -S (O)₂CH₃or-S (O) CH₃。

In some embodiments of the compounds of formulae (I), (II), and (IIIa), L is a bond and R is cyano.

In some embodiments of the compounds of general formulae (I), (II), and (IIIa), R is a 5-6 membered heteroaryl, e.g., furyl, thienyl, thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyranyl, pyrazolyl, pyridyl, pyrimidyl.

In some embodiments of the compounds of formula (I), (II) and (IIIa), R is optionally selected from-OH, C_1-4Alkyl, oxo, -O-C_1-4Alkyl radical, C_3-6Cycloalkyl and 4-6 membered heterocycleA 4-7 membered heterocyclyl substituted with a substituent for a group, for example morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, azetidinyl, pyrrolidinyl, oxetanyl, imidazolyl or piperidinyl optionally substituted with-OH, methyl, oxo, methoxy, isopropoxy, cyclopropyl or oxetanyl.

In some embodiments of the compounds of formula (I), (II) and (IIIa), R is selected from the group consisting of oxetanyl, 3-hydroxyoxetanyl, morpholino, 4-methylpiperazinyl, tetrahydropyranyl, 3-methoxyoxetanyl, 4-methyl-2-oxopiperazinyl, 3-oxomorpholino, 1-methylpiperidinyl, 3-methylmorpholino, 2-methylmorpholino, 4-cyclopropyl-2-oxopiperazinyl, 4- (oxetan-3-yl) -2-oxopiperazinyl, 1-methylimidazolyl and 3-isopropoxyoxetanyl.

In some embodiments of the compounds of formulae (I), (II), and (IIIa), L is a bond and R is-OR³And R is³Is optionally oxo and C_1-4An alkyl-substituted 4-7 membered heterocyclic group. In further embodiments, R³Is tetrahydrothiopyranyl, oxotetrahydrothiopyranyl, piperidyl or 1-methylpiperidinyl.

In some embodiments of the compounds of formulae (I), (II), and (IIIa), R is-S (O)₂NR³R⁴or-C (O) NR³R⁴Wherein R is³And R⁴Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring optionally containing an additional heteroatom selected from N, O and S, such as a morpholine ring, a piperazine ring, a piperidine ring, a thiomorpholine ring, an azetidine ring or a pyrrolidine ring; further, said heterocycle is optionally selected from-OH, C_1-4Alkyl, -O-C_1-4Alkyl, oxo, C_3-6Cycloalkyl and 4-6 membered heterocyclyl, for example morpholino, 4-methylpiperazino, 4-cyclopropylpiperazinyl, 4- (oxetan-3-yl) piperazinyl, oxothiomorpholino, 3-hydroxyazetidinyl, 3-methoxypyrrolidinyl, azetidinyl or methylmorpholino.

In some embodiments of the compounds of formulae (I), (II), and (IIIa), R is-C (O) NR³R⁴Wherein R is³And R⁴One of which is H and the other is C optionally substituted by-OH_1-6An alkyl group.

In some embodiments of the compounds of formulae (I), (II), and (IIIa), R is-C (O) NR³R⁴Wherein R is³And R⁴One of which is H and the other is C optionally substituted by-OH_3-6Cycloalkyl radicals, such as cyclohexyl.

In some embodiments of the compounds of formulae (I), (II), and (IIIa), R is-C (O) NR³R⁴Wherein R is³And R⁴One of which is H and the other is a 4-7 membered heterocyclyl group, such as oxetanyl, piperidinyl or tetrahydropyranyl.

It is to be understood that the definitions of the various groups/substituents for compounds of the general formula (la) in the present invention may be combined with each other, and that the compounds resulting from such combinations are also within the scope of the present invention.

Some embodiments of the invention are compounds of formula (IIIa), wherein:

X¹、X²and X³Are all CH, or X¹And X²Is CH and X³Is N;

G¹is H or halogen;

l is a bond, C_1-6Alkylene or-O-C_1-4An alkylene group;

r is independently selected from cyano, -SF₅、-OR³、-S(O)₂C_1-6Alkyl, -S (O) C_1-6Alkyl, -S (O)₂NR³R⁴、-C(O)OH、-C(O)NR³R⁴、-C(O)NHS(O)₂C_1-6Alkyl, optionally selected from-OH, C_1-4Alkyl, oxo, -O-C_1-4Alkyl radical, C_3-64-7 membered heterocyclyl substituted with substituents of cycloalkyl and 4-6 membered heterocyclyl, or optionally substituted with C_1-4An alkyl-substituted 5-6 membered heteroaryl;

R^aand R^eEach independently selected from halogen;

R³and R⁴Each independently selected from H, C optionally substituted by halogen or-OH_1-6Alkyl, C optionally substituted by-OH_3-7Cycloalkyl, or optionally oxo or C_1-4An alkyl-substituted 4-7 membered heterocyclyl; or, R on the same nitrogen atom³And R⁴Optionally taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclic ring optionally containing an additional heteroatom selected from N, O and S, said heterocyclic ring optionally being selected from-OH, C_1-4Alkyl, -O-C_1-4Alkyl, oxo, C_3-6Cycloalkyl and 4-6 membered heterocyclyl.

Some embodiments of the invention are compounds of formula (IIIa), wherein:

X¹、X²and X³Are all CH;

G¹is H or halogen;

l is a bond or C_1-6Alkylene or-O-C_1-4An alkylene group;

r is independently selected from cyano, -SF₅、-OR³、-S(O)₂C_1-6Alkyl, -S (O) C_1-6Alkyl, -S (O)₂NR³R⁴、-C(O)OH、-C(O)NR³R⁴、-C(O)NHS(O)₂C_1-6Alkyl, optionally selected from-OH, C_1-4Alkyl, oxo, -O-C_1-4Alkyl radical, C_3-64-7 membered heterocyclyl substituted with substituents of cycloalkyl and 4-6 membered heterocyclyl, or optionally substituted with C_1-4An alkyl-substituted 5-6 membered heteroaryl;

R^aand R^eEach independently selected from halogen;

R³and R⁴Each independently selected from H, C optionally substituted by halogen or-OH_1-6Alkyl, C optionally substituted by-OH_3-7Cycloalkyl, or optionally oxo or C_1-4An alkyl-substituted 4-7 membered heterocyclyl; or, R on the same nitrogen atom³And R⁴Optionally taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclic ring optionally containing an additional heteroatom selected from N, O and S, said heterocyclic ring optionally being selected from-OH, C_1-4Alkyl, -O-C_1-4Alkyl, oxo, cyclopropyl and oxetanyl.

Some embodiments of the invention are compounds of formula (IIIa), wherein:

X¹and X²Is CH and X³Is N;

G¹is H or halogen;

l is a bond, C_1-6Alkylene or-O-C_1-4An alkylene group;

r is independently selected from cyano, -SF₅、-OR³、-S(O)₂C_1-6Alkyl, -S (O) C_1-6Alkyl, -S (O)₂NR³R⁴、-C(O)OH、-C(O)NR³R⁴、-C(O)NHS(O)₂C_1-6Alkyl, optionally selected from-OH, C_1-4Alkyl, oxo, -O-C_1-4Alkyl radical, C_3-64-7 membered heterocyclyl substituted with a substituent of cycloalkyl or 4-6 membered heterocyclyl, or optionally substituted with C_1-4An alkyl-substituted 5-6 membered heteroaryl;

R^aand R^eEach independently selected from halogen;

R³and R⁴Each independently selected from H, C optionally substituted by halogen or-OH_1-6Alkyl, C optionally substituted by-OH_3-7Cycloalkyl, or optionally oxo or C_1-4An alkyl-substituted 4-7 membered heterocyclyl; or, R on the same nitrogen atom³And R⁴Optionally taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclic ring optionally containing an additional heteroatom selected from N, O and S, said heterocyclic ring optionally being selected from-OH, C_1-4Alkyl, -O-C_1-4Alkyl, oxo, cyclopropyl and oxetanyl.

Other embodiments of the present invention are compounds of formula (IIIa), wherein:

X¹and X²Is CH and X³Is N;

G¹is H;

l is a bond or C_1-6An alkylene group;

r is independently selected from-OR³、-S(O)₂C_1-6Alkyl, -C (O) OH, -C (O) NR³R⁴Or is optionally selected from C_1-4Substitution of alkyl or oxoA 4-7 membered heterocyclyl substituted with a substituent;

R^aand R^eEach independently selected from halogen;

R³and R⁴Each independently selected from H; or, R on the same nitrogen atom³And R⁴Optionally taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclic ring optionally containing an additional heteroatom selected from N, O and S.

The present invention further relates to compounds of the general formula (I) as defined above, wherein said compounds are selected from the group consisting of:

or pharmaceutically acceptable salts, prodrugs, stable isotopic derivatives, isomers and mixtures thereof.

The compounds of the invention have a significant inhibitory effect on the activity of Janus kinases, particularly TYK 2. The compounds of the present invention are effective in inhibiting the activity of TYK2, preferably the IC thereof₅₀Is 10 to 100nM, more preferably IC₅₀Less than 10nM, most preferably IC₅₀Less than 1 nM. The compound has obvious inhibition effect on the physiological function of TYK2 in NK92 cells.

According to the present invention, the drug may be in any pharmaceutical dosage form including, but not limited to, tablets, capsules, solutions, lyophilized formulations, injections.

The pharmaceutical preparations of the present invention may be administered in dosage units containing a predetermined amount of the active ingredient per dosage unit. Such units may contain, for example, from 0.5 mg to 1g, preferably from 1mg to 700mg, particularly preferably from 5mg to 300mg, of a compound of the invention, depending on the condition to be treated, the method of administration and the age, weight and condition of the patient. Preferred dosage unit formulations are those containing a daily dose or sub-dose, or corresponding fraction thereof, of the active ingredient as indicated above. In addition, pharmaceutical formulations of this type may be prepared using methods well known in the pharmaceutical art.

The pharmaceutical formulations of the invention may be adapted for administration by any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations may be prepared, for example, by combining the active ingredient with one or more excipients or one or more adjuvants using all methods known in the pharmaceutical art.

Synthesis method

The invention also provides a method for preparing the compound. The preparation of the compounds of the general formula (I) according to the invention can be carried out by the following illustrative methods and examples, which should not be construed as limiting the scope of the invention in any way. The compounds of the invention may also be synthesized by synthetic techniques known to those skilled in the art, or a combination of methods known in the art and those described herein may be used. The product from each reaction step is obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatography, and the like. The starting materials and chemicals required for the synthesis can be routinely synthesized or purchased according to the literature (available from SciFinder).

The pyridazine compound shown in the general formula (I) can be synthesized according to the route shown in the method A: 1) the initiator A1 and (hetero) aromatic amine containing functional groups are subjected to substitution reaction to obtain A2; 2) a2 and phenylboronic acid or boric acid ester are subjected to Suzuki coupling reaction to generate A3; 3) hydrolyzing the ester group of A3 into acid, amidating (converting into acyl chloride and coupling with ammonia or directly coupling with ammonia through a condensing agent) to obtain A4, or directly transamination to obtain A4; 4) the functional group of a4 can be further derivatized to yield a number of target compounds according to synthetic methods known in the art.

The method A comprises the following steps:

intermediate a3 was also synthesized according to the route described in method B: a1 is firstly coupled with phenylboronic acid or boric acid ester through Suzuki to generate B2, and then coupled with (hetero) aromatic amine containing functional groups through Buchwald to generate A3.

The method B comprises the following steps:

intermediate a3 can also be synthesized according to the route described in method C: 1) the initiator A1 firstly carries out substitution reaction with benzylamine to obtain C2; 2) c2 and phenylboronic acid or boric acid ester are subjected to Suzuki coupling reaction to generate C3; 3) debenzylation of C3 in acid to give C4; 4) c4 was subjected to substitution or Buchwald coupling to afford A3.

The method C comprises the following steps: