Imidazo[4,5-b]pyridine derivatives useful for the treatment of allergic, inflammatory, metabolic, autoinflammatory, autoimmune, and proliferative diseases

Abstract

The present invention provides compounds according to formula (I), wherein R 1 , R 2 , X1, X2, and X3 are as described herein. The present invention also provides methods for producing such compounds, pharmaceutical compositions containing same, and therapeutic methods using them for the prevention and / or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and / or diseases associated with hypersecretion of IFNα, IL-12, and / or IL-23 by administering the compounds of the invention. [Formula 1] JPEG2026504905000020.jpg73170

Description

[Technical Field]

[0001] The present invention relates to compounds that may be useful in the prevention and / or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and / or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and / or IL-23. Specifically, the compounds of the invention inhibit the Janus kinases (JAKs), a family of tyrosine kinases, more particularly TYK2. The invention also provides methods for producing the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention, and methods for preventing and / or treating allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and / or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and / or IL-23 by administering the compounds of the invention. [Background technology]

[0002] Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transmit cytokine signaling from membrane receptors to STAT transcription factors. Four JAK family members have been described: JAK1, JAK2, JAK3, and TYK2. Upon cytokine binding to its receptor, JAK family members autophosphorylate and / or transphosphorylate each other, subsequently phosphorylating STATs, which then translocate to the nucleus and regulate transcription. JAK-STAT intracellular signaling contributes to the expression of various cytokines and endocrine factors, including interferons, most interleukins, and EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, and PRL (Vainchenker et al., 2008).

[0003] The combined study of genetic models and small-molecule JAK inhibitors has revealed the therapeutic potential of JAK inhibitors (JAKinibs) (Babon et al., 2014). Over the past decade, JAKinibs with varying degrees of selectivity profiles for JAK family members have been developed. While targeting multiple JAKs may not be harmful (Broekman et al., 2011), the development of selective JAKinibs would be highly desirable for developing treatment courses tailored to patient needs, despite the challenges it presents (Fabian et al., 2005). For example, JAK2 inhibition has proven useful in the treatment of polycythemia vera and myelofibrosis, but undesirable effects associated with JAK2 inhibition have been observed (O'Shea and Plenge, 2012). Therefore, compounds with JAK2 inhibitory components are not suitable for the treatment of non-JAK2-mediated diseases.

[0004] Using TYK2 knockout mice, it has been shown that IL-6, IL-10, IL-11, IL-12, IL-13, IL-19, IL-20, IL-22, IL-23, IL-27, IL-28, IL-29, IL-31, IL-35, and / or type 1 interferon signaling are dependent on TYK2 (Schwartz et al., 2016). However, it has recently been shown that JAK1 is the primary driver of IFNα, IL-6, IL-10, and IL-22 signaling, whereas TYK2 is involved in type 1 interferon (including IFNα and IFNβ), IL-23, and IL-12 signaling (Gillooly et al., 2016; Sohn et al., 2013). Because IL-12 and IL-23 activity is particularly increased in patients with autoimmune diseases such as psoriasis and / or inflammatory bowel disorders (O'Shea and Plenge, 2012), selective TYK2 inhibition, while avoiding JAK2-dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling, may be particularly beneficial in treating these diseases (Neubauer et al., 1998; Parganas et al., 1998).

[0005] Furthermore, TYK2 has been reported as a target for multiple autoimmune diseases, providing protection against inflammatory diseases and type 2 diabetes with limited effects on the immune system (Dendrou et al., 2016).

[0006] Thus, there remains a need for new compounds that effectively and selectively inhibit JAK enzymes, particularly TYK2, thus allowing for the design of specific treatments and dosages tailored to disease states. Summary of the Invention

[0007] The present invention relates to compounds useful for the prevention and / or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and / or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and / or IL-23. Specifically, the compounds of the invention inhibit the JAK family of tyrosine kinases, more particularly TYK2. The invention also provides methods for producing the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention, and methods for preventing and / or treating allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and / or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and / or IL-23 by administering the compounds of the invention.

[0008] Thus, in a first aspect of the present invention, there is provided a compound of the present invention having formula I, [ka] During the ceremony, X1 and X2 are independently N or CH; X3 is NR 3 , O, or CR 4a R 4b and R 1 is H or -CH3, R 2 is H or -CH3, R 3 is H or C unsubstituted or substituted with one or more halo 1-2 is alkyl, R 4a and R 4bare independently H, —CN, —N(CH3)2, or —CH2—OH, or a pharmaceutically acceptable salt / co-crystal, or solvate thereof or a solvate of the salt / co-crystal thereof.

[0009] In certain aspects, there is provided a compound of the invention for use in the prevention and / or treatment of, inter alia, allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and / or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and / or IL-23.

[0010] It has further been unexpectedly demonstrated that compounds of the present invention exhibit improved selectivity for TYK2 over other JAK family members, which may be advantageous in the treatment of IFNα, interferon ("interferonopathies", particularly Type I or Type III interferonopathies), IL-12, and / or IL-23 associated diseases, particularly diseases such as systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease.

[0011] Furthermore, the compounds of the present invention and their TYK2 selectivity may be advantageous for patient-specific treatment and tailored dosage design.

[0012] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutical carrier, excipient, or diluent. In certain aspects, the pharmaceutical composition may further comprise an additional therapeutically active ingredient suitable for use in combination with the compound of the present invention. In a more particular embodiment, the further therapeutically active ingredient is a drug for the prevention and / or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations and / or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", in particular type I or type III interferonopathies), IL-12 and / or IL-23, in particular diseases such as systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis and / or Crohn's disease.

[0013] Furthermore, the compounds of the present invention useful in the pharmaceutical compositions and treatment methods disclosed herein are pharmaceutically acceptable when prepared and used.

[0014] In a further aspect of the invention, the invention provides a method of treating a mammal (particularly a human) suffering from a condition selected from those listed herein, in particular an allergic disease, an inflammatory disease, a metabolic disease, an autoinflammatory disease, an autoimmune disease, a proliferative disease, transplant rejection, a disease involving disorders of cartilage metabolism, congenital cartilage malformations, and / or a disease associated with hypersecretion of IFNα, interferons ("interferonopathies", in particular type I or type III interferonopathies), IL-12, and / or IL-23, in particular systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease, which comprises administering an effective amount of a pharmaceutical composition or compound of the invention as described herein.

[0015] The present invention also provides pharmaceutical compositions comprising a compound of the present invention and a suitable pharmaceutical carrier, excipient, or diluent for use in medicine. In certain embodiments, the pharmaceutical composition is for use in the prevention and / or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and / or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies," particularly type I or type III interferonopathies), IL-12, and / or IL-23, particularly diseases such as systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease.

[0016] In an additional aspect, the present invention provides methods for synthesizing the compounds of the present invention using the representative synthetic protocols and routes disclosed later herein.

[0017] Other objects and advantages will become apparent to those skilled in the art from a consideration of the following detailed description.

[0018] It is understood that compounds of the present invention may be metabolized to produce biologically active metabolites. DETAILED DESCRIPTION OF THE INVENTION

[0019] definition The following terms are intended to have the meanings presented below and are useful in understanding the description and intended scope of the present invention.

[0020] In describing the present invention, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings unless otherwise indicated. It should also be understood that, as described herein, any of the moieties defined below may be substituted with various substituents, and that each definition is intended to include such substituted moieties within its scope as described below. Unless otherwise specified, the term "substituted" is defined as set forth below. It should also be understood that the terms "group" and "radical" can be considered interchangeable when used herein.

[0021] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an analog" means one analog or multiple analogs.

[0022] "Alkyl" means a straight or branched chain aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups, such as methyl, ethyl, or propyl, are attached to a linear alkyl chain. Particular alkyl groups include methyl (-CH3), ethyl (-CH2-CH3), n-propyl (-CH2-CH2-CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2-CH2-CH2-CH3), tert-butyl (-CH2-C(CH3)3), sec-butyl (-CH2-CH(CH3)2), n-pentyl (-CH 2- CH 2- CH 2- CH2-CH3), n-hexyl (-CH2-CH2-CH2-CH2-CH2-CH3), and 1,2-dimethylbutyl (-CHCH3)-C(CH3)H 2- CH 2- CH3). Particular alkyl groups have 1 to 4 carbon atoms.

[0023] "Alkenyl" refers to a monovalent olefinic (unsaturated) hydrocarbon radical having the specified number of carbon atoms. Particular alkenyls have 2 to 8 carbon atoms, more particularly 2 to 6 carbon atoms, which may be straight or branched, and have at least 1, and especially 1 to 2, sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (-CH=CH), n-propenyl (-CHCH=CH), isopropenyl (-C(CH)=CH), and the like.

[0024] "Alkoxy" refers to the group O-alkyl, where the alkyl group has the specified number of carbon atoms. Specifically, the term refers to -OC 1-6 refers to an alkyl group. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., having 1 to 6 carbon atoms. Further particular alkoxy groups have 1 to 4 carbon atoms.

[0025] "Aryl" refers to a monovalent aromatic hydrocarbon group derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular, aryl refers to a monocyclic or fused polycyclic aromatic ring structure having the specified number of ring atoms. Specifically, the term includes groups containing 6 to 10 ring members. Particular aryl groups include phenyl and naphthyl.

[0026] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). Particular halo groups are either fluoro or chloro.

[0027] "Substituted" refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).

[0028] As used herein, the term "substituted with one or more" refers to 1 to 4 substituents. In one embodiment, it refers to 1 to 3 substituents. In a further embodiment, it refers to 1 or 2 substituents. In yet a further embodiment, it refers to 1 substituent.

[0029] "Pharmaceutically acceptable" means approved or approved by a regulatory authority of the federal or state government or corresponding agency of a country other than the United States, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, and more specifically, in humans.

[0030] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present invention that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts (formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphor acid, etc.) or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion) or coordinates with an organic base (ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.). Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, if the compound contains a basic functional group, include salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.

[0031] "Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient, or carrier with which a compound of the invention is administered.

[0032] "Prodrug" refers to a compound containing derivatives of the compounds of the present invention that have cleavable groups and become pharmaceutically active in vivo by solvolysis or under physiological conditions. Examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like.

[0033] "Solvate" refers to a form of a compound that is associated with a solvent, usually through solvolysis. This physical association involves hydrogen bonding. Conventional solvents include water, EtOH, acetic acid, and the like. The compounds of the present invention may be prepared, for example, in crystalline form, and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric and non-stoichiometric solvates. In certain cases, a solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0034] A "subject" includes a human. The terms "human," "patient," and "subject" are used interchangeably herein.

[0035] "An effective amount" means the amount of a compound of the present invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "effective amount" may vary depending on the compound, the disease and its severity, and the age, weight, etc. of the subject being treated.

[0036] "Preventing" or "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder (i.e., preventing at least one of the clinical symptoms of the disease from developing in a subject who may be exposed to a disease-causing agent or who may be predisposed to the disease prior to the onset of the disease).

[0037] The term "prophylaxis" is related to "prevention" and refers to a measure or procedure that aims to prevent, rather than treat or cure, a disease. Non-limiting examples of preventive measures may include the administration of a vaccine, the administration of low molecular weight heparin to hospital patients who are at risk of thrombosis due to immobility, and the administration of an antimalarial agent such as chloroquine before visiting a geographic area where malaria is endemic or there is an increased risk of contracting malaria.

[0038] "Treating" or "treatment" of any disease or disorder, in one embodiment, refers to ameliorating the disease or disorder (i.e., halting the disease or reducing the sign, extent, or severity of at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treating" refers to modulating the disease or disorder, either physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In a further embodiment, "treating" or "treatment" relates to slowing the progression of the disease.

[0039] As used herein, the term "allergic disease" refers to a group of conditions characterized by hypersensitivity disorders of the immune system, including allergic airway diseases (e.g., asthma, rhinitis), sinusitis, eczema, and urticaria, as well as food allergies or allergies to insect venom.

[0040] As used herein, the term "asthma" refers to a pulmonary disorder characterized by altered pulmonary gas flow associated with airway narrowing of any cause (intrinsic, extrinsic, or both, allergic or non-allergic). The term asthma may be used with one or more adjectives to indicate the cause.

[0041] As used herein, the term "inflammatory disease" refers to a group of conditions including rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway diseases (e.g., asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory liver diseases (e.g., primary biliary cholangitis (PBC) and / or primary sclerosing cholangitis (PSC)), inflammatory bowel diseases (e.g., Crohn's disease, ulcerative colitis), endotoxin-driven disease states (e.g., complications after bypass surgery or chronic endotoxin states that contribute to chronic heart failure), and related diseases involving cartilage, such as joints. In particular, the term refers to rheumatoid arthritis, osteoarthritis, allergic airway diseases (e.g., asthma), chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease. More specifically, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel disease. Most specifically, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease.

[0042] As used herein, the term "metabolic disease" refers to a group of conditions involving the body's ability to process certain nutrients and vitamins. Metabolic disorders include phenylketonuria (PKU), type II diabetes, hyperlipidemia, gout, and rickets. Specific examples of metabolic disorders are type II diabetes and / or obesity.

[0043] As used herein, the term "autoinflammatory disease" refers to a group of diseases including cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndromes (TRAPS), Behcet's disease, systemic juvenile idiopathic arthritis (SJIA), and Still's disease.

[0044] As used herein, the term "autoimmune disease" refers to a group of diseases including COPD, asthma (e.g., intrinsic asthma, extrinsic asthma, dust-related asthma, infantile asthma), particularly chronic or refractory asthma (e.g., late-onset asthma and airway hyperresponsiveness), bronchitis including bronchial asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, dermatomyositis, Sjogren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type 1 diabetes and its associated complications, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto's thyroiditis and autoimmune thyroiditis), contact dermatitis and further eczematous dermatitis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), interferon-related diseases, atherosclerosis, and obstructive airway diseases including amyotrophic lateral sclerosis. In particular, the term refers to COPD, asthma, systemic lupus erythematosus, type I diabetes, interferonopathy, and inflammatory bowel disease.

[0045] As used herein, the term "proliferative disease" refers to conditions such as cancer (e.g., uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (e.g., polycythemia vera, essential thrombocythemia, and myelofibrosis), leukemia (e.g., acute myeloid leukemia, acute and chronic lymphoblastic leukemia), multiple myeloma, psoriasis, restenosis, scleroderma, or fibrosis. In particular, the term refers to cancer, leukemia, multiple myeloma, and psoriasis.

[0046] As used herein, the term "cancer" refers to a malignant or benign growth of cells in the skin or body organs, for example, but not limited to, the breast, prostate, lung, kidney, pancreas, stomach, or intestine. Cancers tend to invade adjacent tissues and spread (metastasize) to distant organs, such as the bone, liver, lung, or brain. As used herein, the term "cancer" includes both metastatic tumor cell types (including, but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mast cell tumor) and tissue cancer types (including, but not limited to, colon cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, kidney cancer, stomach cancer, glioblastoma, primary liver cancer, ovarian cancer, prostate cancer, and uterine leiomyosarcoma). In particular, the term "cancer" includes acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumor, endometrial cancer, endothelial carcinoma, ependymoblastoma, ependymoma, esophageal cancer, Ewing's sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, Gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor (endocrine pancreas), Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt's lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphomaNon-Hodgkin's lymphoma, lymphoma, Waldenstrom's hypergammaglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, oral cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, non-pharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papilloma, parathyroid cancer, penile cancer, pharyngeal cancer, moderately differentiated pineal parenchymal tumor, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary This refers to blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing's sarcoma family of tumors, Kaposi's sarcoma, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's hypergammaglobulinemia, and Wilms' tumor.

[0047] As used herein, the term "leukemia" refers to neoplastic diseases of the blood and blood-forming organs. Such diseases can cause bone marrow and immune system dysfunction, making the host highly susceptible to infection and bleeding. In particular, the term "leukemia" refers to acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic lymphoblastic leukemia (CLL).

[0048] As used herein, the term "transplant rejection" refers to acute or chronic rejection of cells, tissues, or solid organs, for example, pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, nervous tissue, heart, lung, combined cardiopulmonary, kidney, liver, intestine, pancreas, trachea, or esophagus, or graft-versus-host disease.

[0049] As used herein, the term "diseases involving disorders of cartilage metabolism" includes osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, painful osteodystrophy, Tietze's syndrome or costochondritis, fibromyalgia, osteochondritis, neuropathic or neuropathic arthritis, joint disorders, endemic forms of arthritis (such as endemic osteoarthritis, Musereni's disease, and Handigodu's disease), degeneration due to fibromyalgia, fibromyalgia, systemic lupus erythematosus, scleroderma, and degeneration due to ankylosing spondylitis. In certain embodiments, the term refers to ankylosing spondylitis.

[0050] As used herein, the term "congenital cartilage malformations" includes conditions such as hereditary chondrolysis, chondrodysplasia, and pseudochondrodysplasia, particularly, but not limited to, microtia, anotia, metaphyseal chondrodysplasia, and related disorders.

[0051] As used herein, diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly Type I or Type III interferonopathies), IL-12, and / or IL-23 include diseases such as systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren's syndrome, psoriasis, rheumatoid arthritis, multiple sclerosis, trisomy 21, psoriatic arthritis, ulcerative colitis, and / or Crohn's disease.

[0052] "Compounds of the invention," and equivalent expressions, where the context allows, are meant to include compounds of formula (e) as described herein, including pharmaceutically acceptable salts, and solvates, such as hydrates and solvates of pharmaceutically acceptable salts. Similarly, references to intermediates, whether or not they themselves are claimed, are meant to include their salts and solvates, where the context allows.

[0053] Where ranges are recited herein (for example, but not limited to, C1-8 alkyl), the recitation of a range should be considered a representation of each and every member of that range.

[0054] Other derivatives of the compounds of the present invention are active in both their acid and acid-derivative forms, although the acid-sensitive forms often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (Bundgard, H, 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from the acidic groups pendant on the compounds of the present invention are particularly useful prodrugs. In some cases, it may be desirable to prepare double ester prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. In particular, such prodrugs are useful as prodrugs of the C1-8 alkyl, C2-8 alkenyl, C6- 10 optionally substituted aryl, and (C- 10 Aryl)-(C 1-4 alkyl) esters.

[0055] The present disclosure includes all isotopic forms of the compounds of the present invention provided herein, whether in (i) a form in which all atoms of a given atomic number have a mass number (or mixture of mass numbers) that is predominant in nature (referred to herein as a "natural isotopic form"), or in (ii) a form in which one or more atoms have the same atomic number but a mass number that is different from the mass number of the atom that is predominant in nature (referred to herein as a "non-natural variant isotopic form"). It is understood that atoms may naturally exist as a mixture of mass numbers. The term "non-natural variant isotopic form" also includes embodiments in which the proportion of atoms of a given atomic number that have mass numbers that are less common in nature (referred to herein as "uncommon isotopes") is increased compared to that occurring in nature, for example, to a level of >20%, >50%, >75%, >90%, >95%, or >99% by atomic number of that atomic number (the latter embodiment being referred to as an "isotopically enriched variant form"). The term "non-natural variant isotopic form" also includes embodiments in which the proportion of an uncommon isotope is reduced compared to that occurring in nature. Isotopic forms can include radioactive forms (i.e., incorporating a radioactive isotope) and non-radioactive forms. Radioactive forms are typically isotopically enriched variant forms.

[0056] Therefore, non-natural variant isotopic forms of a compound may contain deuterium ( 2 H or D), carbon-11 ( 11 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-15( 15 N), oxygen-15( 15 O), oxygen-17( 17 O), oxygen-18( 18 O), phosphorus-32( 32 P), sulfur-35( 35 S), chlorine-36( 36 Cl), chlorine-37( 37 Cl), fluorine-18( 18 F) Iodine-123( 123 I), iodine-125( 125It may contain one or more artificial or uncommon isotopes, such as I), or may contain an increased proportion of the isotope in one or more atoms compared to the proportion that predominates in nature.

[0057] Non-natural variant isotopic forms containing radioactive isotopes may be used, for example, in drug and / or substrate tissue distribution studies. The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. 2 Non-natural variant isotopic forms incorporating 1H or 2D may offer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. 11 C. 18 F, 15 0, and 13 Non-natural variant isotopic forms can be prepared incorporating positron-emitting isotopes, such as N, and may be useful in positron emission topography (PET) studies to examine substrate receptor occupancy.

[0058] It should also be understood that compounds that have the same molecular formula but that differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0059] Stereoisomers that are not mirror images of one another are called "diastereomers," while stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0060] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure and differ in the replacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the shifting of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are also formed by treatment with acid or base.

[0061] Tautomeric forms may be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

[0062] The compounds of the present invention may possess one or more asymmetric centers. Accordingly, such compounds may be produced as individual (R) or (S) stereoisomers or as mixtures thereof.

[0063] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures thereof, racemic or otherwise. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0064] It is understood that compounds of the present invention may be metabolized to produce biologically active metabolites.

[0065] The present invention The present invention relates to compounds that may be useful in the prevention and / or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and / or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies," particularly type I or type III interferonopathies), IL-12, and / or IL-23, in particular diseases such as systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease. Specifically, the compounds of the present invention inhibit the JAK family of tyrosine kinases, more particularly TYK2. The invention also provides methods for producing the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention, and methods for preventing and / or treating diseases such as allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and / or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and / or IL-23, particularly systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease, by administering the compounds of the invention.

[0066] Thus, in a first aspect of the present invention, there is provided a compound of the present invention having formula I, [ka] During the ceremony, X1 and X2 are independently N or CH; X3 is NR 3 , O, or CR 4a R 4b and R 1 is H or -CH3, R 2 is H or -CH3, R 3 is H or C unsubstituted or substituted with one or more halogen atoms 1-2 is alkyl, R 4a and R 4b are independently H, —CN, —N(CH3)2, or —CH2—OH, or a pharmaceutically acceptable salt / co-crystal, or solvate thereof or a solvate of the salt / co-crystal thereof.

[0067] R 1 , R 2 , R 3 , R 4a , R 4b , X1, X2, and X3, in any combination thereof, are as set forth below.

[0068] Preferably, X1 is N.

[0069] Preferably, X2 is N.

[0070] Preferably, X3 is NR 3 , or O.

[0071] Most preferably, X3 is O.

[0072] Preferably, R 1 is H.

[0073] Preferably, R 2 is H.

[0074] Preferably, R 3 is H, or C unsubstituted or substituted with one or more independently selected F, Cl, or Br; 1-2It is alkyl.

[0075] More preferably, R 3 is H, or C unsubstituted or substituted with one or more independently selected F or Cl; 1-2 It is alkyl.

[0076] Even more preferably, R 3 is H or C unsubstituted or substituted with one or more F 1-2 It is alkyl.

[0077] Even more preferably, R 3 is H, -CH3, -CH2CH3, -CHF2, -CF3, -CH2CHF2, or -CH2CF3.

[0078] Most preferably, R 3 is H, —CH3, or —CH2CF3.

[0079] Preferably, R 4a and R 4b are independently H, —CN, —N(CH3)2, or —CH2—OH.

[0080] More preferably, R 4a and R 4b are independently H, —CN, or —N(CH 3 ) 2 .

[0081] Even more preferably, R 4a and R 4b are independently H or —CN.

[0082] Most preferably, R 4a is H and R 4b is -CN.

[0083] Embodiments according to the present invention are provided as described below.

[0084] Embodiment 1 provides a compound of formula I as defined above.

[0085] Embodiment 2 is R 1 is H.

[0086] Embodiment 3 is R 2 is H.

[0087] Embodiment 4 provides a compound of any one of embodiments 1-3, wherein X 1 is N.

[0088] Embodiment 5 provides a compound of any one of embodiments 1-4, wherein X2 is N.

[0089] Embodiment 6 is R 4a and R 4b is independently H, —CN, —N(CH 3 ) 2 , or —CH 2 —OH.

[0090] Embodiment 7 is R 4a and R 4b is independently H, —CN, or —N(CH 3 ) 2 .

[0091] Embodiment 8 is R 4a and R 4b is independently H or —CN.

[0092] Embodiment 9 is R 4a is H and R 4b The compound of any one of embodiments 1-8 is provided, wherein is —CN.

[0093] Embodiment 10 is a case in which X3 is NR 3 or O.

[0094] Embodiment 11 is R 3is H, or C unsubstituted or substituted with one or more independently selected F, Cl, or Br; 1-2 The compound of any one of embodiments 1-10 is provided, wherein R is alkyl.

[0095] Embodiment 12 is R 3 is H, or C unsubstituted or substituted with one or more independently selected F or Cl 1-2 The compound of any one of embodiments 1 to 11 is provided, wherein R is alkyl.

[0096] Embodiment 13 is R 3 is H, or C unsubstituted or substituted with one or more F 1-2 The compound of any one of embodiments 1 to 12 is provided, wherein R is alkyl.

[0097] Embodiment 14 is R 3 is H, -CH3, -CH2CH3, -CHF2, -CF3, -CH2CHF2, or -CH2CF3.

[0098] Embodiment 15 is R 3 is H, —CH 3 , or —CH 2 CF 3 .

[0099] Embodiment 16 provides a compound of any one of embodiments 1 to 15, wherein X3 is O.

[0100] A preferred group of compounds according to the invention are compounds of formula I-1, which are compounds of formula I, wherein X1 is N or CH, X2 is N, and X3 is NR 3 , O, or CR 4a R 4b and R 1 is H or -CH3, and R 2 is H or -CH3, and R 3 is H or C unsubstituted or substituted with one or more halo 1-2 alkyl, and R4a and R 4b are independently H, —CN, —N(CH3)2, or —CH2—OH.

[0101] A further preferred group of compounds according to the invention are compounds of formula I-2, which are compounds of formula I, in which X1 is N or CH, X2 is N and X3 is NR 3 , O, or CR 4a R 4b and R 1 is H or -CH3, and R 2 is H and R 3 is H or C unsubstituted or substituted with one or more halo 1-2 alkyl, and R 4a and R 4b are independently H, —CN, —N(CH3)2, or —CH2—OH.

[0102] A further preferred group of compounds according to the invention are compounds of formula I-3, which are compounds of formula I, wherein X1 is N, X2 is N and X3 is NR 3 , O, or CR 4a R 4b and R 1 is H or -CH3, and R 2 is H and R 3 is H or C unsubstituted or substituted with one or more halo 1-2 alkyl, and R 4a and R 4b are independently H, —CN, —N(CH3)2, or —CH2—OH.

[0103] A further preferred group of compounds according to the invention are compounds of formula I-4, which are compounds of formula I, wherein X1 is N, X2 is N and X3 is NR 3 , O, or CR 4a R 4b and R 1 is H and R 2 is H and R 3 is H or C unsubstituted or substituted with one or more halo 1-2 alkyl, and R4a and R 4b are independently H, —CN, —N(CH3)2, or —CH2—OH.

[0104] A further preferred group of compounds according to the invention are compounds of formula I-5, which are compounds of formula I, wherein X1 is N, X2 is N and X3 is NR 3 , O, or CR 4a R 4b and R 1 is H and R 2 is H and R 3 is H, or C unsubstituted or substituted with one or more independently selected F, Cl, or Br; 1-2 alkyl, and R 4a and R 4b are independently H, —CN, —N(CH3)2, or —CH2—OH.

[0105] A further preferred group of compounds according to the invention are compounds of formula I-6, which are compounds of formula I, wherein X1 is N, X2 is N and X3 is NR 3 , O, or CR 4a R 4b and R 1 is H and R 2 is H and R 3 is H, or C unsubstituted or substituted with one or more independently selected F or Cl; 1-2 alkyl, and R 4a and R 4b are independently H, —CN, or —N(CH 3 ) 2 .

[0106] A further preferred group of compounds according to the invention are compounds of formula I-7, which are compounds of formula I, wherein X1 is N, X2 is N, and X3 is NR 3 , O, or CR 4a R 4b and R 1 is H and R 2 is H and R 3is H, -CH3, -CH2CH3, -CHF2, -CF3, -CH2CHF2, or -CH2CF3, and R 4a and R 4b are independently H or —CN.

[0107] A further preferred group of compounds according to the invention are compounds of formula I-8, which are compounds of formula I, wherein X1 is N, X2 is N and X3 is NR 3 , O, or CR 4a R 4b and R 1 is H and R 2 is H and R 3 is H, -CH3, or -CH2CF3, and R 4a is H and R 4b is -CN.

[0108] A further preferred group of compounds according to the invention are compounds of formula I-9, which are compounds of formula I, wherein X1 is N, X2 is N, and X3 is NR 3 or O and R 1 is H and R 2 is H and R 3 is H, —CH3, or —CH2CF3.

[0109] In one embodiment, the compound of the invention is 5-((7-((6-(2,3-dihydro-4H-1,4-oxazin-4-yl)pyridazin-3-yl)amino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)-4-methylpicolinonitrile.

[0110] In one embodiment, the compound of the invention is: [ka]

[0111] In one embodiment, the compounds of the invention are provided in natural isotopic form.

[0112] In one embodiment, the compounds of the present invention are provided in non-natural variant isotopic forms. In certain embodiments, the non-natural variant isotopic forms are deuterium (i.e., 2 In one embodiment, the atoms of the compounds of the present invention are in a form in which hydrogen atoms (H or D) are incorporated, and hydrogen atoms are specified in the chemical structure at one or more atoms of the compounds of the present invention. In one embodiment, the atoms of the compounds of the present invention are in a non-radioactive isotopic form. In one embodiment, one or more atoms of the compounds of the present invention are in a radioactive isotopic form. Preferably, the radioisotope is a stable isotope. Preferably, the non-natural variant isotopic form is a pharmaceutically acceptable form.

[0113] In one embodiment, compounds of the invention are provided in which a single atom of the compound exists in a non-natural variant isotopic form, hi another embodiment, compounds of the invention are provided in which two or more atoms exist in a non-natural variant isotopic form.

[0114] Non-natural isotopically variant forms may generally be prepared by conventional techniques known to those of skill in the art or by processes described herein (e.g., by processes similar to those described in the accompanying Examples for preparing natural isotopically variant forms). Thus, non-natural isotopically variant forms may be prepared by substituting appropriate isotopically variant (or labeled) reagents for the conventional reagents used in the Examples.

[0115] In one embodiment, the compounds of the invention are not isotopically variants.

[0116] In one aspect, the compounds of the invention according to any one of the embodiments described herein are present as the free base.

[0117] In one aspect, the compounds of the invention according to any one of the embodiments described herein are pharmaceutically acceptable salts.

[0118] In one aspect, the compound of the invention according to any one of the embodiments described herein is a solvate of the compound.

[0119] In one aspect, the compound of the invention according to any one of the embodiments described herein is a solvate of a pharmaceutically acceptable salt of the compound.

[0120] Although the groups specified for each embodiment are generally listed separately above, the compounds of the present invention include any or each embodiment in the above formula, as well as other formulas presented herein, selected from one or more of the particular members or groups specified for each variable. Thus, the present invention is intended to include all combinations of such embodiments within its scope.

[0121] Although the particular groups for each embodiment are generally listed separately above, compounds of the invention can be those in which one or more variables (e.g., R groups) are selected from one or more embodiments according to any of formula (e) listed above. Thus, the invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.

[0122] Alternatively, excluding one or more of the named variables from any group or embodiment, or combination thereof, is also contemplated by the present invention.

[0123] In certain embodiments, the present invention provides prodrugs and derivatives of the compounds described in the formula above. Prodrugs are derivatives of the compounds of the present invention that have metabolically cleavable groups and become pharmaceutically active in vivo by solvolysis or under physiological conditions. Examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like.

[0124] Other derivatives of the compounds of the present invention are active in both their acid and acid-derivative forms, although the acid-labile forms often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (Bundgard, H, 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds of the present invention are preferred prodrugs. In some cases, it may be desirable to prepare double ester prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Particularly useful are C1-C8 alkyl, C2-C8 alkenyl, aryl, C7-C8 alkyl, C8-C8 alkyl, C9-C9 alkyl, C10-C8 alkyl, C11-C8 alkyl, C12-C8 alkyl, C13-C8 alkyl, C14-C8 alkyl, C15-C8 alkyl, C16-C8 alkyl, C17-C8 alkyl, C18-C8 alkyl, C19-C8 alkyl, C20-C8 alkyl, C21-C8 alkyl, C22-C22 alkyl, C23-C24 alkyl, C24-C26 alkyl, C25-C26 alkyl, C26-C26 alkyl, C27-C28 alkyl, C28-C28 alkyl, C29 ... 12 Substituted aryl and C7-C 12 It is an aryl alkyl ester.

[0125] Pharmaceutical Compositions Formulation 1 - Tablets The compound of the invention according to Formula I can be mixed as a dry powder with a dry gelatin binder in about a 1:2 weight ratio. A small amount of magnesium stearate can be added as a lubricant. The mixture can be formed into 240-270 mg tablets (80-90 mg of the active compound of the invention according to Formula I per tablet) in a tablet press.

[0126] Formulation 2 - Capsules The compound of the invention according to Formula I can be mixed as a dry powder with a starch diluent in about a 1:1 weight ratio, and the mixture can be filled into 250 mg capsules (125 mg of the active compound of the invention according to Formula I per capsule).

[0127] Formulation 3 - Liquid A compound of the invention according to Formula I (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), the resulting mixture can be blended, passed through a No. 10 mesh US sieve, and then mixed with a pre-made aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg). Sodium benzoate (10 mg), flavor, and color can be diluted with water and added with stirring. Sufficient water can then be added with stirring. Sufficient water can then be added to bring the total volume to 5 mL.

[0128] Formulation 4 - Tablets The compound of the invention according to Formula I can be mixed as a dry powder with a dry gelatin binder in about a 1:2 weight ratio. A small amount of magnesium stearate can be added as a lubricant. The mixture can be formed into 450-900 mg tablets (150-300 mg of the active compound of the invention according to Formula I) in a tablet press.

[0129] Formulation 5 - Injection The compounds of the invention according to Formula I can be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg / mL.

[0130] Formulation 6 - Topical Stearyl alcohol (250 g) and white petrolatum (250 g) can be dissolved at about 75° C. Then, a mixture of a compound of the invention according to Formula I (50 g), methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) can be added, and the resulting mixture can be stirred until it solidifies.

[0131] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent.

[0132] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent, wherein the other therapeutic agent is a therapeutic agent for an allergic disease, an inflammatory disease, a metabolic disease, an autoinflammatory disease, an autoimmune disease, a proliferative disease, transplant rejection, a disease involving disorders of cartilage metabolism, congenital cartilage malformations, and / or a disease associated with hypersecretion of IFNα, interferon ("interferonopathies," particularly Type I or Type III interferonopathies), IL-12, and / or IL-23. In a more particular embodiment, the other therapeutic agent is a therapeutic agent for an inflammatory disease, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and / or a disease associated with hypersecretion of IFNα, interferon ("interferonopathies," particularly Type I or Type III interferonopathies), IL-12, and / or IL-23.

[0133] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent, wherein the other therapeutic agent is an agent for treating an allergic disorder. In a particular embodiment, the other therapeutic agent is an agent for treating asthma.

[0134] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent, wherein the other therapeutic agent is an agent for treating an inflammatory disease. In particular embodiments, the other therapeutic agent is an agent for treating rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and / or inflammatory bowel disease. In more particular embodiments, the other therapeutic agent is an agent for treating rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and / or inflammatory bowel disease.

[0135] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent, wherein the other therapeutic agent is an agent for treating a metabolic disorder. In certain embodiments, the other therapeutic agent is an agent for treating type II diabetes and / or obesity.

[0136] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent, wherein the other therapeutic agent is an agent for treating an autoinflammatory disease. In certain embodiments, the other therapeutic agent is an agent for treating cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndromes (TRAPS), Behcet's disease, systemic juvenile idiopathic arthritis (SJIA), and / or Still's disease.

[0137] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent, wherein the other therapeutic agent is an agent for treating an autoimmune disease, hi certain embodiments, the other therapeutic agent is an agent for treating COPD, asthma, systemic lupus erythematosus, type 1 diabetes, interferonopathy, and / or inflammatory bowel disease.

[0138] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent, wherein the other therapeutic agent is an agent for treating a proliferative disorder, hi certain embodiments, the other therapeutic agent is an agent for treating cancer, leukemia, multiple myeloma, and / or psoriasis.

[0139] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent, wherein the other therapeutic agent is an agent for treating transplant rejection. In a particular embodiment, the other therapeutic agent is an agent for treating graft-versus-host disease.

[0140] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent, wherein the other therapeutic agent is an agent for treating a disease involving a disorder of cartilage metabolism. In a particular embodiment, the other therapeutic agent is an agent for treating ankylosing spondylitis.

[0141] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent, wherein the other therapeutic agent is an agent for treating a congenital cartilage malformation. In certain embodiments, the other therapeutic agent is an agent for treating microtia, anotia, and / or metaphyseal chondrodysplasia.

[0142] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent, where the other therapeutic agent is an agent for treating a disease associated with hypersecretion of IFNα, interferon ("interferonopathy," particularly Type I or Type III interferonopathy), IL-12, and / or IL-23. In particular embodiments, the other therapeutic agent is an agent for treating systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease.

[0143] Compounds for Use in Therapy and Methods of Treatment In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in medicine. In a particular embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prophylaxis and / or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and / or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and / or IL-23, particularly diseases such as systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease. In a more particular embodiment, the present invention provides a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, for use in the prophylaxis and / or treatment of inflammatory diseases, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and / or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly Type I or Type III interferonopathies), IL-12, and / or IL-23, in particular diseases such as systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease.

[0144] In another embodiment, the invention provides the use of a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, in the manufacture of a medicament for the prevention and / or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and / or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and / or IL-23. In a more particular embodiment, the present invention provides the use of a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, in the manufacture of a medicament for the prevention and / or treatment of inflammatory diseases, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and / or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly Type I or Type III interferonopathies), IL-12, and / or IL-23, in particular diseases such as systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease.

[0145] In another embodiment, the invention provides a method for the prevention and / or treatment of a mammal suffering from an allergic disease, an inflammatory disease, a metabolic disease, an autoinflammatory disease, an autoimmune disease, a proliferative disease, transplant rejection, a disease involving disorders of cartilage metabolism, congenital cartilage malformations, and / or a disease associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly type I or type III interferonopathies), IL-12, and / or IL-23, the method comprising the administration of an effective amount of one or more of the compounds of the invention or pharmaceutical compositions described herein for the treatment or prevention of the condition. In more particular embodiments, the present invention provides a method for the prevention and / or treatment of a mammal suffering from inflammatory diseases, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and / or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", particularly Type I or Type III interferonopathies), IL-12, and / or IL-23, particularly diseases such as systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease, which method comprises the administration of an effective amount of one or more of the compounds of the invention or pharmaceutical compositions described herein for the treatment or prevention of the condition.

[0146] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of an allergic disease. In a particular embodiment, the allergic disease is asthma.

[0147] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for the prevention and / or treatment of an allergic disease. In a particular embodiment, the allergic disease is asthma.

[0148] In another embodiment, the present invention provides a method for the prevention and / or treatment of a mammal suffering from an allergic disease, the method comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the condition. In a particular embodiment, the allergic disease is asthma.

[0149] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of an inflammatory disease. In a specific embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel disease. In a more specific embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease.

[0150] In another embodiment, the present invention provides use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for the prevention and / or treatment of an allergic disease. In certain embodiments, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel disease. In more specific embodiments, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease.

[0151] In another embodiment, the present invention provides a method for the prevention and / or treatment of a mammal suffering from an inflammatory disease, the method comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the condition. In certain embodiments, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and / or inflammatory bowel disease. In more specific embodiments, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease.

[0152] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of a metabolic disease. In a particular embodiment, the metabolic disease is type II diabetes and / or obesity.

[0153] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for the prevention and / or treatment of a metabolic disease. In a particular embodiment, the metabolic disease is type II diabetes and / or obesity.

[0154] In another embodiment, the present invention provides a method for the prevention and / or treatment of a mammal suffering from a metabolic disease, the method comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the condition. In certain embodiments, the metabolic disease is type II diabetes and / or obesity.

[0155] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of an autoimmune disease. In particular embodiments, the autoimmune disease is COPD, asthma, systemic lupus erythematosus, type 1 diabetes, interferonopathy, and inflammatory bowel disease.

[0156] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for the prevention and / or treatment of an autoimmune disease, hi certain embodiments, the autoimmune disease is COPD, asthma, systemic lupus erythematosus, type 1 diabetes, interferonopathy, and inflammatory bowel disease.

[0157] In another embodiment, the present invention provides a method for the prevention and / or treatment of a mammal suffering from an autoimmune disease, the method comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the condition. In certain embodiments, the autoimmune disease is COPD, asthma, systemic lupus erythematosus, type 1 diabetes, interferonopathy, and inflammatory bowel disease.

[0158] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of an autoinflammatory disease. In a particular embodiment, the autoinflammatory disease is cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndromes (TRAPS), Behcet's disease, systemic juvenile idiopathic arthritis (SJIA), or Still's disease.

[0159] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for the prevention and / or treatment of an autoinflammatory disease. In certain embodiments, the autoinflammatory disease is cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndromes (TRAPS), Behcet's disease, systemic juvenile idiopathic arthritis (SJIA), or Still's disease.

[0160] In another embodiment, the present invention provides a method for the prevention and / or treatment of a mammal suffering from an autoinflammatory disease, the method comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the condition. In certain embodiments, the autoinflammatory disease is cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndromes (TRAPS), Behcet's disease, systemic juvenile idiopathic arthritis (SJIA), or Still's disease.

[0161] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of a proliferative disease. In particular embodiments, the proliferative disease is cancer, leukemia, multiple myeloma, and psoriasis.

[0162] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for the prevention and / or treatment of a proliferative disease. In certain embodiments, the proliferative disease is cancer, leukemia, multiple myeloma, and psoriasis.

[0163] In another embodiment, the present invention provides a method for the prevention and / or treatment of a mammal suffering from a proliferative disease, the method comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the condition. In certain embodiments, the proliferative disease is cancer, leukemia, multiple myeloma, and psoriasis.

[0164] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of transplant rejection. In a particular embodiment, the transplant rejection is graft-versus-host disease.

[0165] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for the prevention and / or treatment of transplant rejection, hi a particular embodiment, the transplant rejection is graft-versus-host disease.

[0166] In another embodiment, the present invention provides a method for the prevention and / or treatment of a mammal suffering from transplant rejection, the method comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the condition. In certain embodiments, the transplant rejection is graft-versus-host disease.

[0167] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of a disease associated with a disorder of cartilage metabolism. In a particular embodiment, the disease associated with a disorder of cartilage metabolism is ankylosing spondylitis.

[0168] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for the prevention and / or treatment of a disease associated with a disorder of cartilage metabolism, hi a particular embodiment, the disease associated with a disorder of cartilage metabolism is ankylosing spondylitis.

[0169] In another embodiment, the present invention provides a method for the prevention and / or treatment of a mammal suffering from a disease associated with a disorder of cartilage metabolism, the method comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the condition. In a particular embodiment, the disease associated with a disorder of cartilage metabolism is ankylosing spondylitis.

[0170] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of a congenital cartilage malformation. In a particular embodiment, the congenital cartilage malformation is selected from microtia, anotia, and / or metaphyseal chondrodysplasia.

[0171] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for the prevention and / or treatment of a congenital cartilage malformation, hi certain embodiments, the congenital cartilage malformation is selected from microtia, anotia, and / or metaphyseal chondrodysplasia.

[0172] In another embodiment, the present invention provides a method for the prevention and / or treatment of a mammal suffering from a congenital cartilage malformation, the method comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the condition. In certain embodiments, the congenital cartilage malformation is selected from microtia, anotia, and / or metaphyseal chondrodysplasia.

[0173] In one embodiment, the present invention provides a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention, for use in the prevention and / or treatment of a disease associated with hypersecretion of IFNα, interferon ("interferonopathies", particularly Type I or Type III interferonopathies), IL-12, and / or IL-23. In a particular embodiment, the disease associated with hypersecretion of IFNα, interferon ("interferonopathies", particularly Type I or Type III interferonopathies), IL-12, and / or IL-23 is systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease.

[0174] In another embodiment, the invention provides use of a compound of the invention or a pharmaceutical composition comprising a compound of the invention in the manufacture of a medicament for the prevention and / or treatment of a disease associated with hypersecretion of IFNα, interferon ("interferonopathies", particularly Type I or Type III interferonopathies), IL-12, and / or IL-23. In particular embodiments, the disease associated with hypersecretion of IFNα, interferon ("interferonopathies", particularly Type I or Type III interferonopathies), IL-12, and / or IL-23 is systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease.

[0175] In another embodiment, the present invention provides a method for the prevention and / or treatment of a mammal suffering from a disease associated with hypersecretion of IFNα, interferon ("interferonopathy," particularly Type I or Type III interferonopathy), IL-12, and / or IL-23, the method comprising the administration of an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the condition. In certain embodiments, the disease associated with hypersecretion of IFNα, interferon ("interferonopathy," particularly Type I or Type III interferonopathy), IL-12, and / or IL-23 is systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease.

[0176] Injection dose levels range from about 0.1 mg / kg / h to at least 10 mg / kg / h, all for about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. The maximum total dose is expected to not exceed about 1 g / day for a 40-80 kg human patient.

[0177] For the prevention and / or treatment of long-term conditions, such as degenerative conditions, treatment regimens may extend over several months or years, with oral administration being preferred for patient convenience and tolerability. For oral administration, a typical regimen is one to four times daily, particularly one to three times daily, typically one to two times daily, and most typically once daily. Alternatively, for drugs with long-lasting effects, oral administration once every two weeks, once weekly, and once daily are typical regimens. In particular, the administration regimen may be every 1 to 14 days, more specifically every 1 to 10 days, even more specifically every 1 to 7 days, and most specifically every 1 to 3 days.

[0178] Using these administration patterns, each dose provides from about 1 to about 1000 mg of a compound of the invention, with particular doses each providing from about 10 to about 500 mg, particularly from about 30 to about 250 mg.

[0179] Transdermal doses are generally selected to provide blood levels similar to or lower than those achieved using injection doses.

[0180] When used to prevent the onset of a condition, the compounds of the invention are administered at the dosage levels described above, typically under the advice and supervision of a physician, to patients at risk of developing the condition. Patients at risk of developing a particular condition generally include those with a family history of the condition or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0181] The compounds of the invention can be administered as the sole active agent or in combination with other therapeutic agents, including other solid forms of the invention that exhibit the same or similar therapeutic activity and that have been determined to be safe and effective for such co-administration. In certain embodiments, co-administration of two (or more) agents can allow significantly lower doses of each to be used, thereby reducing the side effects observed.

[0182] In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament. In certain embodiments, the pharmaceutical composition further comprises an additional active ingredient.

[0183] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of an inflammatory disease. Specific agents include, but are not limited to, immunomodulators such as azathioprine, corticosteroids (e.g., prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, mycophenolate mofetil, muromonab-CD3 (OKT3, e.g., Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.

[0184] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of arthritis (e.g., rheumatoid arthritis). Specific agents include analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, synthetic DMARDs (e.g., but not limited to, methotrexate, leflunomide, sulfasalazine, auranofin, gold sodium thiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, tofacitinib, baricitinib, filgotinib, upadacitinib, fostamatinib, and cyclosporine), and biologic DMARDs (e.g., but not limited to, infliximab, etanercept, adalimumab, rituximab, and abatacept).

[0185] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of a proliferative disorder. Specific agents include methotrexate, leucovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubine, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibodies (e.g., Herceptin™), capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g., Iressa®, In certain embodiments, the proliferative disorder is selected from cancer, myeloproliferative disorders, and leukemia.

[0186] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of an autoimmune disease. Specific agents include, but are not limited to, glucocorticoids, cytostatics (e.g., purine analogs), alkylating agents (e.g., nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds, and others), antimetabolites (e.g., methotrexate, azathioprine, and mercaptopurine), cytotoxic antibiotics (e.g., dactinomycin anthracycline, mitomycin C, bleomycin, and mithramycin), antibodies (e.g., anti-CD20, anti-CD25, or anti-CD3 (OTK3) monoclonal antibodies, Atgam®, and Thymoglobuline®), cyclosporine, tacrolimus, rapamycin (sirolimus), interferons (e.g., IFN-β), TNF-binding proteins (e.g., infliximab, etanercept, or adalimumab), mycophenolate, fingolimod, and myriocin.

[0187] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of transplant rejection. Specific agents include, but are not limited to, calcineurin inhibitors (e.g., cyclosporine or tacrolimus (FK506)), mTOR inhibitors (e.g., sirolimus, everolimus), antiproliferative agents (e.g., azathioprine, mycophenolic acid), corticosteroids (e.g., prednisolone, hydrocortisone), antibodies (e.g., monoclonal anti-IL-2Rα receptor antibodies, basiliximab, daclizumab), polyclonal anti-T cell antibodies (e.g., antithymocyte globulin (ATG), antilymphocyte globulin (ALG)).

[0188] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of asthma and / or rhinitis and / or COPD. Specific agents include, but are not limited to, β2-adrenergic receptor agonists (e.g., salbutamol, levalbuterol, terbutaline, and bitolterol), epinephrine (inhaled or tablet), anticholinergics (e.g., ipratropium bromide), and glucocorticoids (oral or inhaled). Long-acting beta-2 agonists (e.g., salmeterol, formoterol, bambuterol, and sustained-release oral albuterol), inhaled steroid and long-acting bronchodilator combinations (e.g., fluticasone / salmeterol, budesonide / formoterol), leukotriene antagonists and synthesis inhibitors (e.g., montelukast, zafirlukast, and zileuton), mediator release inhibitors (e.g., cromoglycate and ketotifen), biological modulators of IgE responses (e.g., omalizumab), antihistamines (e.g., cetirizine, cinnarizine, fexofenadine), and vasoconstrictors (e.g., oxymetazoline, xylometazoline, naphazoline, and tramazoline).

[0189] Additionally, compounds of the invention may be administered in combination with emergency therapies for asthma and / or COPD, including oxygen or heliox administration, nebulized salbutamol or terbutaline, optionally in combination with an anticholinergic (e.g., ipratropium), systemic steroids (oral or intravenous, e.g., prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, nonspecific beta-agonists, injected or inhaled (e.g., epinephrine, isoetharine, isoproterenol, metaproterenol), anticholinergics (IV or nebulized, e.g., glycopyrrolate, atropine, ipratropium), methylxanthines (theophylline, aminophylline, bamifylline), inhaled anesthetics with bronchodilatory effects (e.g., isoflurane, halothane, enflurane), ketamine, and intravenous magnesium sulfate.

[0190] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of inflammatory bowel disease (IBD). Specific agents include, but are not limited to, glucocorticoids (e.g., prednisone, budesonide), synthetic disease-modifying agents, immunomodulators (e.g., methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine, and cyclosporine), and biologic disease-modifying agents, immunomodulators (infliximab, adalimumab, rituximab, and abatacept).

[0191] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of SLE. Specific agents include, but are not limited to, human monoclonal antibodies (belimumab (Benlysta)), disease-modifying antirheumatic drugs (DMARDs), such as antimalarials (e.g., Plaquenil, hydroxychloroquine), immunosuppressants (e.g., methotrexate and azathioprine), cyclophosphamide and mycophenolic acid, immunosuppressants and analgesics (e.g., nonsteroidal anti-inflammatory drugs), opiates (e.g., dextropropoxyphene and co-codamol), opioids (e.g., hydrocodone, oxycodone, MS Contin, or methadone), and fentanyl duragesic transdermal patches.

[0192] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of psoriasis. Specific agents include bath solutions, moisturizers, medicated creams and ointments containing coal tar, dithranol (anthralin), corticosteroids (desoximethasone (Topicort™), fluocinonide, vitamin D3 analogs (e.g., calcipotriol), argan oil, and retinoids (etretinate, acitretin, tazarotene), systemic treatments (e.g., methotrexate, cyclosporine, retinoids, thioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil, azathioprine, benzodiazepines, benzocaine, benzodiazepines), and the like. These include, but are not limited to, topical treatments such as oprin, tacrolimus, fumarates, or biologics (e.g., Amevive™, Enbrel™, Humira™, Remicade™, Raptiva™, and ustekinumab (an IL-12 and IL-23 blocker)). Additionally, the compounds of the present invention may be administered in combination with other therapies, including, but not limited to, phototherapy or photochemotherapy (e.g., psoralens and ultraviolet A phototherapy (PUVA)).

[0193] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of an allergic reaction. Specific agents include, but are not limited to, antihistamines (e.g., cetirizine, diphenhydramine, fexofenadine, levocetirizine), glucocorticoids (e.g., prednisone, betamethasone, beclomethasone, dexamethasone), epinephrine, theophylline, or antileukotrienes (e.g., montelukast or zafirlukast), anticholinergics, and decongestants.

[0194] As will be understood by those skilled in the art, simultaneous administration includes any means of delivering two or more therapeutic agents to patients as part of the same treatment regimen.Two or more agents can be administered simultaneously in a single formulation, i.e., a single pharmaceutical composition, but this is not necessary.The agents can be administered in different formulations at different times.

[0195] Chemical synthesis procedure General The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0196] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art (Greene, TW; Wuts, PGM;, 1991).

[0197] The following methods are presented together with detailed and comparative examples for the preparation of the compounds of the invention defined above. The compounds of the invention can be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.

[0198] All reagents were commercial grade and used as is without further purification unless otherwise noted. Commercially available anhydrous solvents were used for reactions performed under an inert atmosphere. Reagent-grade solvents were used in all other cases unless otherwise noted. Column chromatography was performed on silica gel 60 (35-70 μm). Thin-layer chromatography was performed using precoated silica gel F-254 plates (0.25 mm thick). 1 1 H NMR spectra were recorded on a Bruker Avance II Ultrashield 400 NMR spectrometer (400 MHz). 1Chemical shifts (δ) for H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (δ 0.00) or the appropriate residual solvent peak, i.e., CHCl (δ 7.27), as an internal reference. Multiplicities are given as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broadband (br). Electrospray MS spectra were acquired on an Agilent 1260 Infinity LC / MSD spectrometer or an Agilent 1290 Infinity II LC / MSD spectrometer, both coupled to Agilent DAD, PDA, and MSD (ESI pos / neg) detectors. Columns used were: Waters XSelect CSH C18 3.5 μm, 2.1 mm i.d. × 30 mm length, and Waters XSelect CSH XP C18 2.5 μm, 2.1 mm i.d. × 50 mm length. The method uses a MeCN / H2O gradient (H2O containing 10 mM (NH4)HCO3, or both MeCN and H2O containing 0.1% formic acid). [Table 1]

[0199] Synthetic Preparation of the Compounds of the Invention General synthesis method The compounds of the present invention can be prepared from readily available starting materials according to the syntheses and procedures described below, or those described in paragraphs 56 to 149 of WO2019 / 076716, or syntheses and procedures similar thereto, although procedures generally known in the art are also contemplated (including those described in March's Advanced Organic Chemistry, 8th edition March 2020, ISBN: 978-1-119-37180-9, John Wiley & Sons).

[0200] Certain compounds of the present invention can be made according to the following schemes. [ka]

[0201] 1.1. Intermediate 1 [ka] Morpholin-3-one (CAS No. 109-11-5, 9.5 g, 1.0 equiv.), 3,6-dibromopyridazine (CAS No. 17973-86-3, 24.6 g, 1.1 equiv.), and KPO (39.9 g, 2.0 equiv.) were mixed in dry 1,4-dioxane (190 mL) and purged with argon for 10 minutes. After the addition of DMEDA (0.8 g, 1.0 mL, 0.10 equiv.) and copper(I) iodide (0.9 g, 0.05 equiv.), the mixture was purged with argon for 15 minutes and stirred at 110 °C for 4.5 hours. The mixture was cooled to 80 °C, and the solid was filtered and rinsed with THF. The filtrate was concentrated to give Intermediate 1. LCMS: MW (calc): 258.1; m / z MS (mes): 257.9 / 259.9 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (d, 1H), 8.02 (d, 1H), 4.33 (s, 2H), 4.10 - 4.00 (m, 4H)

[0202] 1.2. Intermediate 2 [ka] To crude intermediate 1 (24 g, 1.0 equiv.) in dry THF (1 L) under an argon atmosphere was added 1 M diisobutylaluminum hydride in hexanes (141 mL, 1.5 equiv.) at −78° C., and the reaction mixture was stirred for 1.5 h. The reaction mixture was diluted with MeOH (100 mL) and concentrated in vacuo to give intermediate 2. LCMS: MW (calc): 260.1; m / z MS (mes): 260.0 / 262.0 [M+H] +

[0203] 1.3. Intermediate 3 [ka] To a solution of crude intermediate 2 (24.45 g, 1.0 equiv.) in DCM (1 L) was added AlCl (21.93 g, 1.75 equiv.) at room temperature, and the mixture was stirred for 20 h. Saturated aqueous Rochelle's salt solution (200 mL) was added. The solid was filtered off, the layers were separated, and the aqueous layer was extracted with DCM (3 × 300 mL). The combined organic layers were concentrated in vacuo. The residue was purified by flash column chromatography (eluting with heptane / EtOAc 100 / 0 to 25 / 75) to give intermediate 3. LCMS: MW (calc): 242.1; m / z MS (mes): 242.0 / 244.0 [M+H] + 1 H NMR (400 MHz, CDCl3) δ 7.37 (d, 1H), 6.81 (d, 1H), 6.21 (d, 1H), 6.16 (d, 1H), 4.26 - 4.18 (m, 2H), 4.07 - 3.96 (m, 2H) [Table 2]

[0204] Illustrative Examples 1.4.Compound 1 [ka] Intermediate 4 (2.88 g, 1.1 equiv.), Intermediate 3 (2.0 g, 1.0 equiv.), CsCO (8.08 g, 3.0 equiv.), and water (0.15 mL, 1.0 equiv.) were mixed in dry DMF (80 mL) and purged with argon for 15 min. After the addition of JosiPhos SL-J009-1 (CAS No. 158923-11-6, 0.098 g, 0.022 equiv.) and Pd(cinnamyl)Cl (CAS No. 12131-44-1, 0.043 g, 0.010 equiv.), the mixture was purged with argon for 10 min and stirred at 110 °C for 16 h. Aqueous workup, purification by flash column chromatography (eluent: DCM (0% to 8% MeOH)), and lyophilization afforded Cpd1. LCMS: MW (calc): 441.5; m / z MS (mes): 442.2 [M+H] +

[0205] Additional compounds of the present invention may be made by similar processes and / or techniques known to those skilled in the art. [Table 3] [Table 4] [Table 5]

[0206] Biological Examples Example 2. In vitro assay 2.1. JAK1 Inhibition Assay JAK1 Ulight-JAK1 Peptide Assay Inhibition of human JAK1 was tested with the JAK1 human TK kinase enzyme radiometric assay [Km ATP], KinaseProfiler assay at Eurofins Discovery (Eurofins Cerep SA, Celle-L'Evescault, France; catalogue no. 14-918KP).

[0207] Protocol Recombinant human JAK1 (catalytic domain, amino acids 866–1154; UNIPROT no. P23458) was incubated in 20 mM Tris / HCl (pH 7.5), 0.2 mM EDTA, 500 μM GEEPLYWSFPAKKK, 10 mM magnesium acetate, and [γ- 33 The reaction mixture was incubated with [P]-ATP (specific activity and concentration as required). The reaction was initiated by adding the Mg / ATP mixture. After a 40-minute incubation at room temperature, the reaction was stopped by adding phosphoric acid to a concentration of 0.5%. 10 μL of the reaction mixture was then spotted onto a P30 filtermat and washed four times for 4 minutes in 0.425% phosphoric acid and once in MeOH before drying and scintillation counting.

[0208] 2.2. JAK2 Inhibition Assay JAK2 Ulight-JAK1 Peptide Assay Inhibition of human JAK2 was tested with the JAK2 Human TK Kinase Enzyme Radiometric Assay [Km ATP], KinaseProfiler assay at Eurofins Discovery (Eurofins Cerep SA, Celle-L'Evescault, France; catalogue no. 14-640KP).

[0209] Protocol Recombinant human JAK2 (catalytic domain, amino acids 808–1132; UNIPROT no. O60674) was incubated in 8 mM MOPS (pH 7.0, 0.2 mM EDTA, 100 μM KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC, 10 mM magnesium acetate, and [γ- 33 The reaction mixture was incubated with [P]-ATP (specific activity and concentration as required). The reaction was initiated by adding the Mg / ATP mixture. After a 40-minute incubation at room temperature, the reaction was stopped by adding phosphoric acid to a concentration of 0.5%. 10 μL of the reaction mixture was then spotted onto a P30 filtermat and washed four times for 4 minutes in 0.425% phosphoric acid and once in MeOH before drying and scintillation counting.

[0210] JAK3 Inhibition Assay Inhibition of human JAK3 was tested with the JAK3 Human TK Kinase Enzyme Radiometric Assay [Km ATP], KinaseProfiler assay at Eurofins Discovery (Eurofins Cerep SA, Celle-L'Evescault, France; catalogue no. 14-629KP).

[0211] Protocol Recombinant human JAK3 (catalytic domain, amino acids 781–1124; UNIPROT number P52333) was incubated in 8 mM MOPS (pH 7.0, 0.2 mM EDTA, 500 μM GGEEEEYFELVKKKK, 10 mM magnesium acetate, and [γ- 33 The reaction mixture was incubated with [P]-ATP (specific activity and concentration as required). The reaction was initiated by adding the Mg / ATP mixture. After a 40-minute incubation at room temperature, the reaction was stopped by adding phosphoric acid to a concentration of 0.5%. 10 μL of the reaction mixture was then spotted onto a P30 filtermat and washed four times for 4 minutes in 0.425% phosphoric acid and once in MeOH before drying and scintillation counting.

[0212] TYK2 Inhibition Assay Inhibition of human TYK2 was tested with the TYK2 human TK kinase enzyme radiometric assay [Km ATP], KinaseProfiler assay at Eurofins Discovery (Eurofins Cerep SA, Celle-L'Evescault, France; catalogue no. 14-924KP).

[0213] Protocol Recombinant human TYK2 (catalytic domain, amino acids 875–1187; UNIPROT number P29597) was incubated in 8 mM MOPS (pH 7.0, 0.2 mM EDTA, 250 μM GGMEDIYFEFMGGKKK, 10 mM magnesium acetate, and [γ- 33The reaction mixture was incubated with [P]-ATP (specific activity and concentration as required). The reaction was initiated by adding the Mg / ATP mixture. After a 40-minute incubation at room temperature, the reaction was stopped by adding phosphoric acid to a concentration of 0.5%. 10 μL of the reaction mixture was then spotted onto a P30 filtermat and washed four times for 4 minutes in 0.425% phosphoric acid and once in MeOH before drying and scintillation counting. [Table 6]

[0214] 2.5. Conclusion The in vitro assay data reported above demonstrate the selectivity of exemplary compounds of the invention for TYK2 over other JAK family members (JAK1, JAK2, JAK3).

[0215] Furthermore, the in vitro assay data reported above demonstrate that exemplary compounds of the present invention provide additional selectivity for JAK2 compared to the comparator compounds, while maintaining TYK2 potency and selectivity for JAK3.

[0216] Example 3. Selectivity Assay To determine the selectivity of exemplary compounds of the present invention, inhibition of specific pathways is measured.

[0217] Notably, both IFNα and IL-12 signaling are TYK2-dependent, but IFNα can also be inhibited by JAK1-selective inhibitors. However, activation of STAT1 by IL-6 is strictly dependent on JAK1.

[0218] 3.1. Cellular Assay IFNα activation of STAT1 in PBMCs Protocol Peripheral blood mononuclear cells (PBMCs) are isolated from the buffy coat under sterile conditions by density gradient centrifugation using LymphoPrep™ medium (Axis-Shield, catalog no. 1114545), followed by two subsequent washing steps with PBS (Sigma, catalog no. P4417-100TAB). After these two washing steps, the cell pellet is dissolved in ammonium chloride buffer (1.5 M NH4Cl, 100 mM NaHCO3, and 10 mM Na2EDTA) to lyse red blood cells. The cells are then centrifuged, and the PBMCs are resuspended in plain RPMI-1640 medium (Lonza, catalog no. BE12-115F / U1) containing 10% (v / v) heat-inactivated FBS (Sigma Aldrich, catalog no. F7524).

[0219] Immediately after isolation, PBMCs are seeded into 96-well plates at 1.0E06 cells / well in 180 μL of RPMI-1640 containing 10% (v / v) FBS.

[0220] PBMCs are treated with test compounds for 30 minutes at 37°C, 5% CO2. 0.6 μL of 333x concentrated compound dilutions are added to wells using a Mosquito. After 30 minutes of test compound / vehicle pretreatment, PBMCs are stimulated with recombinant human IFNα (PeproTech, Cat. No. 300-02A) at a final concentration of 5 ng / mL by adding 20 μL (10x concentrated) cytokine trigger, for 30 minutes at 37°C, 5% CO2, to obtain a final volume of 200 μL per well.

[0221] All compounds are tested singly starting at 30 μM followed by a 1 / 3 serial dilution, for a total of 10 doses (30 μM, 10 μM, 3.3 μM, 1.11 μM, 0.370 μM, 0.123 μM, 0.0412 μM, 0.0137 μM, 0.0046 μM, and 0.0015 μM) (final DMSO concentration 0.3%).

[0222] Thirty minutes after cytokine stimulation, 200 μL of the cell suspension was transferred to a 96-well V-bottom plate and centrifuged at 1000 rpm for 5 minutes to pellet the cells, followed by removal of the supernatant. The cell pellet was reconstituted in 100 μL of 1× lysis buffer supplemented with an EDTA-free protease inhibitor cocktail (Roche Applied Sciences, Product No. 11836170001), and the sample was then frozen and stored at -80°C. The 1× lysis buffer was provided in the Phospho-STAT1 ELISA kit and contained phosphatase inhibitors. Endogenous phosphorylated STAT1 levels were quantified using a 96-well PathScan® Phospho-STAT1 (Tyr701) Sandwich ELISA Kit (Cell Signaling, Product No. 7234) according to the manufacturer's instructions.

[0223] HRP activity (HRP conjugated to the secondary antibody) is measured by adding 100 μL of freshly prepared luminol substrate (BM Chemiluminescent ELISA Substrate (POD), Roche, product number 11582950001), incubating for 5 min at room temperature in the dark, and measuring on an Envision (Perkin Elmer) (100 msec integration time).

[0224] 3.1.1.2.Results A positive control (CAS No. 1187594-09-7, 10 μM in vehicle) and a negative control (vehicle, 0% inhibition) are used to calculate "percent inhibition (PIN)" values.

[0225] Percent inhibition is calculated as follows:

number

[0226] RCLU (vehicle control): relative chemiluminescence signal determined in the presence of vehicle and trigger

[0227] RCLU (test compound): relative chemiluminescence signal determined in the presence of test compound and trigger

[0228] RCLU (positive control): relative chemiluminescence signal determined in the presence of a positive control and a trigger

[0229] PIN values ​​were plotted for compounds tested in a dose response and nonlinear regression (sigmoidal) curve fitting was applied using GraphPad Prism software to determine the mean IC 50 Derive a value.

[0230] 3.2. Human Whole Blood Assay (hWBA) 3.2.1.Materials Lithium Heparin Vacutainer® Tubes (Becton Dickinson and Co., Catalog No. 367880)

[0231] RPMI-1640 medium (Capricorn Scientific GmbH, catalog number RPMI-HXA)

[0232] Bovine serum albumin (Merck KGaA, Catalog No. A3059)

[0233] DPBS, calcium-free, magnesium-free, 1× (Thermo Fisher Scientific Inc., catalog number 14190)

[0234] Human universal type I IFNα (Pestka Biomedical Laboratories, Inc., catalog number 11200-1)

[0235] Recombinant human IL-2 protein (R&D Systems Inc., Cat. No. 202-IL-010)

[0236] Recombinant human IL-6 protein (R&D Systems Inc., Cat. No. 206-IL-010)

[0237] Recombinant human GM-CSF protein (R&D Systems Inc., Cat. No. 215-GM-010)

[0238] Lysis / fixation buffer, 5x (Becton Dickinson and Co., catalog number 558049)

[0239] PE mouse anti-STAT1 (pY701), clone 4a antibody (Becton Dickinson and Co., catalog number 562069)

[0240] Alexa Fluor® 647 Mouse Anti-STAT3 (pY705), Clone 4 / P-STAT3 Antibody (Becton Dickinson and Co., Cat. No. 557815)

[0241] PE mouse anti-STAT5(pY694), clone 47 / Stat5(pY694) antibody (Becton Dickinson and Co., catalog number 612567)

[0242] V500 mouse anti-human CD4, clone RPA-T4 antibody (Becton Dickinson and Co., catalog number 560768)

[0243] CD33 APC, clone P67.6 antibody (Becton Dickinson and Co., catalog number 345800)

[0244] Falcon® 5 mL polypropylene round-bottom tubes (Corning Inc., catalog number 352063)

[0245] Falcon® 96-well polystyrene round-bottom microplate (Corning Inc., catalog number 351177)

[0246] SL40R Centrifuge (Thermo Fisher Scientific Inc.)

[0247] Attune NxT flow cytometer (Thermo Fisher Scientific Inc.)

[0248] 3.2.2. Method Human whole blood was collected in lithium heparin tubes and incubated at 37°C for 30 minutes to stabilize before the assay was initiated.

[0249] Compounds were thawed and 10 serially diluted pre-dilutions in DMSO were prepared from the compound stock solution by transferring 10 μL of the highest concentration stock solution to 20 μL of DMSO (3× serial dilution). Compound working solutions (10× concentrated) were then prepared in RPMI-1640 medium by transferring 20 μL of the pre-diluted compound in DMSO to 180 μL of RPMI-1640 medium. 10 μL of each diluted compound (10× concentrated) was added to a 5 mL round-bottom tube, followed by the addition of 100 μL of whole blood. The whole blood was incubated with the compound on an orbital rocker at 37°C for 30 minutes. DMSO was used as a vehicle control.

[0250] IFNα trigger: Recombinant human IFNα was thawed on ice and diluted to 5500 U / mL in PBS + 0.1% BSA in a 1.5 mL Eppendorf tube (polypropylene). 10 μL of trigger or vehicle was added to the tube containing whole blood to obtain the final test concentration (500 U / mL). The whole blood was incubated with the trigger for 20 minutes at 37°C on an orbital rocker.

[0251] IL-2 trigger: Recombinant human IL-2 was thawed on ice and diluted to 330 ng / mL in PBS + 0.1% BSA in a 1.5 mL Eppendorf tube (polypropylene). To obtain the final test concentration (30 ng / mL), 10 μL of trigger or vehicle (PBS + 0.1% BSA) was added to the tube containing whole blood. The whole blood was gently mixed and incubated with the trigger for 30 minutes at 37°C on an orbital rocker.

[0252] IL-6 trigger: Recombinant human IL-6 was thawed on ice and diluted to 8.8 ng / mL in PBS + 0.1% BSA in a 1.5 mL Eppendorf tube (polypropylene). To obtain the final test concentration (0.8 ng / mL), 10 μL of trigger or vehicle (PBS + 0.1% BSA) was added to the tube containing whole blood. The whole blood was gently mixed and incubated with the trigger for 20 minutes at 37°C on an orbital rocker.

[0253] GM-CSF trigger: Recombinant human GM-CSF was thawed on ice and diluted to 220 pg / mL in PBS + 0.1% BSA in a 1.5 mL Eppendorf tube (polypropylene). To obtain a final test concentration (20 pg / mL), 10 μL of trigger or vehicle (PBS + 0.1% BSA) was added to the tube containing whole blood. The whole blood was gently mixed and incubated with the trigger for 20 minutes at 37°C on an orbital rocker.

[0254] Following the trigger incubation, 1 mL of freshly prepared, prewarmed 1x lysis / fixation buffer was added to the whole blood. The sample was vortexed, 1 mL of buffer was added, and the sample was vortexed again to ensure complete RBC lysis. The tube was incubated in a water bath at 37°C for 10 minutes. The cells were pelleted by centrifugation at 500 x g for 8 minutes at room temperature, the tube was inverted, and the supernatant was discarded. The cell pellet was resuspended in 2 mL of DPBS and centrifuged at 500 x g for 8 minutes at room temperature. The tube was again inverted, the supernatant was discarded, and 900 μL of ice-cold MeOH was added dropwise to the cells with gentle agitation on a vortex. The tube was locked and stored at -20°C until further use for labeling and flow cytometry analysis.

[0255] After permeabilization (-20°C in MeOH), cells were pelleted by centrifugation at 500 x g for 8 minutes at room temperature, the tube was inverted, and the supernatant was removed. The cell pellet was washed by adding 2 mL of PBS + 3% BSA and vortexing. Cells were pelleted by centrifugation at 500 x g for 8 minutes at room temperature. The tube was inverted again, and the supernatant was removed.

[0256] The cells were transferred to a 96-well plate and an antibody cocktail for staining was added. -IFNα and IL-6 trigger group: 5 μL of CD4-V500 and pSTAT1-PE antibodies, and 20 μL of pSTAT3-AF647 antibody were added to each well. - IL-2 trigger group: 5 μL of CD4-V500 and 20 μL of pSTAT5-PE antibody were added to each well. - GM-CSF trigger group: 5 μL of CD33-APC and 20 μL of pSTAT5-PE antibody were added to each well.

[0257] Samples were incubated in the dark for 1 hour at room temperature. At the end of the incubation, samples were washed with DPBS by adding 100 μL of DPBS to each well, pelleted by centrifugation at 500 × g for 8 minutes at room temperature, and the supernatant was removed by flicking the plate. The wash step was repeated by adding 200 μL of DPBS to each well and centrifuging at 500 × g for 8 minutes at room temperature. After the final wash, cells were resuspended in 240 μL of DPBS, and 120 μL (half of the suspension) from each well was transferred to a new plate as a technical replicate. 120 μL of DPBS was added to each well of both plates, and the samples were resuspended by pipetting. One plate was immediately used for analysis on the Attune flow cytometer, and the second plate was stored at 4 °C until analysis was complete and safely discarded.

[0258] Data Analysis On the Attune flow cytometer, cells were gated within the P1 gate (FSC-A vs. SSC-A plot) and 13,000 events in this gate was set as the stop option for sample collection.

[0259] Data were further analyzed in FlowLogic software by gating CD4+ / CD33+ cells within the P2 gate (SSC-A vs. CD4 / CD33). From P2, histogram plots of the pSTAT proteins of interest (according to trigger group) were generated. Unstimulated vehicle samples from each donor were used to set the gate for pSTAT in a manner that included less than 1% positive events. The percentage of pSTAT-positive cells was exported to MS Excel and percent inhibition (PIN) values ​​were calculated. IC 50 For determination of PIN, PIN values ​​were plotted against log compound concentration in GraphPad Prism software.

[0260] 3.2.4.Results Using the above protocol, the following results were obtained: [Table 7]

[0261] 3.3. Conclusion While JAK1 is a major driver of IFNα, IL-6, IL-10, and IL-22 signaling, TYK2 is involved in type I interferon (including IFNα and IFNβ), IL-23, and IL-12 signaling (Gillooly et al., 2016; Sohn et al., 2013). The whole blood assay data reported above demonstrate selective inhibition of TYK2-dependent pathways by exemplary compounds of the invention. In particular, at least 7.7-fold higher potency was recorded for exemplary compounds of the invention against the IFNα-induced pathway than the IL-6-induced pathway, thus confirming the TYK2 selectivity of the compounds of the invention over JAK2.

[0262] Example 4. In vivo assay 4.1. Mouse model of psoriasis-like epidermal hyperplasia induced by intradermal injection of IL-22 or IL-23 4.1.1.Materials Mouse recombinant IL-22 (582-ML-CF) (carrier-free) was provided by R&D systems. Mouse recombinant IL-23 (14-8231, CF) (carrier-free) was provided by e-Bioscience.

[0263] 4.1.2.Animals Balb / c mice (female, weighing 18-20 g) were obtained from CERJ (France). Mice were maintained on a 12-hour light / dark cycle (07:00-19:00). Temperature was maintained at 22°C, and food and water were provided ad libitum.

[0264] 4.1.3. Research design The design of this study was adapted from Rizzo et al., 2011.

[0265] On the first day (D1), shave the hair around both ears of the mice.

[0266] For four consecutive days (D1–D4), mice were administered murine recombinant IL-22 or IL-23 (1 μg / 20 μL in PBS / 0.1% BSA) intradermally in the right ear and 20 μL of PBS / 0.1% BSA in the left ear daily under anesthesia induced by inhalation of isoflurane.

[0267] From D1 to D5, mice are administered test compound (3, 10, 30, or 100 mg / kg orally daily in MC 0.5%) or vehicle 1 hour before injection of IL-23 / IL-22.

[0268] 4.1.4. Disease assessment The thickness of both ears is measured daily with an automatic caliper. Body weight is assessed at baseline and at sacrifice. On day 5, 2 hours after the last dose, the mice are sacrificed. The ear pinnae are cut free of cartilage. The pinnae are weighed and then placed in a vial containing 1 mL of RNAlater solution or formaldehyde.

[0269] Blood samples are also collected from the retro-orbital sinus on D4 for PK profiling immediately before dosing (T0) and at 1, 3, and 6 hours post-dose.

[0270] There were 10 mice per group. Results are expressed as mean ± standard error and statistical analysis was performed using one-way ANOVA followed by Dunnett's post-hoc test (vs. IL-22 or IL-23 vehicle groups).

[0271] 4.1.5.Histology: After sacrifice, ears were harvested and fixed in 3.7% formaldehyde before being embedded in paraffin. 2 μm thick sections were prepared and stained with hematoxylin and eosin. Ear epidermal thickness was measured by image analysis (Sis'Ncom software), and six images per ear were captured at ×20 magnification. Data were expressed as mean ± standard error, and statistical analysis was performed using one-way ANOVA followed by Dunnett's post-hoc test (vs. IL-22 or IL-23 vehicle groups).

[0272] 4.1.6. RNA extraction, RT-PCR, and real-time PCR Transcription levels of IL-17a, IL-22, IL-1β, LCN2, and S100A9 in ear tissue are determined using real-time quantitative PCR.

[0273] lastly Those skilled in the art will appreciate that the foregoing description is exemplary and explanatory in nature and is intended to illustrate the present invention and its preferred embodiments. Through routine experimentation, those skilled in the art will recognize that obvious modifications and variations can be made without departing from the spirit of the present invention. All such modifications that come within the scope of the appended claims are intended to be included therein. It is therefore intended that the present invention be defined not by the foregoing description, but by the following claims and their equivalents.

[0274] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in this specification as if fully set forth.

[0275] It is understood that factors such as differences in the cell penetration abilities of various compounds may contribute to discrepancies between the activity of compounds in in vitro biochemical and cellular assays.

[0276] At least some of the chemical names of the compounds of the invention provided and described in this application may have been generated on an automated basis using commercially available chemical naming software programs and have not been independently verified. Exemplary programs that perform this function include the Lexichem naming tool sold by Open Eye Software, Inc. and the Autonom software tool sold by MDL, Inc. In the event that the depicted chemical name and the depicted structure differ, the depicted structure shall control.

[0277] References Babon, JJ, Lucet, IS, Murphy, JM, Nicola, NA, Varghese, LN, 2014. The molecular regulation of Janus kinase (JAK) activation. Biochem.J. 462, 1-13. https: / / doi.org / 10.1042 / BJ20140712 Broekman, F., Giovannetti, E., Peters, GJ, 2011. Tyrosine kinase inhibitors: Multi-targeted or single-targeted? WorldJ.Clin. Oncol. 2, 80-93. https: / / doi.org / 10.5306 / wjco.v2.i2.80 Dendrou, C.A., Cortes, A., Shipman, L., Evans, H.G., Attfield, K.E., Jostins, L., Barber, T., Kaur, G., Kuttikkatte, S.B., Leach, OA, Desel, C., Faergeman, S.L., Cheeseman, J., Neville, M.J., Sawcer, S., Compston, A., Johnson, A.R., Everett, C., Bell, J.I. Karpe, F., Ultsch, M., Eigenbrot, C., McVean, G., Fugger, L., 2016. Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity. Sci.Transl. Med.8, 363ra149. https: / / doi.org / 10.1126 / scitranslmed.aag1974 Fabian, MA, Biggs, WH, Treiber, DK, Atteridge, CE, Azimioara, MD, Benedetti, MG, Carter, TA, Ciceri, P., Edeen, PT, Floyd, M., Ford, JM, Galvin, M., Gerlach, JL, Grotzfeld, RM, Herrgard, S., Insko, DE, Insko, MA, Lai, AG, Lelias, J.-M., Mehta, SA, Milanov, ZV, Velasco, AM, Wodicka, LM, Patel, HK, Zarinkar, PP, Lockhart, DJ, 2005. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat.Biotechnol. 23, 329-336. https: / / doi.org / 10.1038 / nbt1068 Gillooly, K., Zhang, Y., Yang, X., Zupa-Fernandez, A., Cheng, L., Strnad, J., Cunningham, M., Heimrich, E., Zhou, X., Chen, J., Chaudhry, C., Li, S., McIntyre, K., Carman, J., Moslin, R., Wrobleski, S., Weinstein, D., Burke, J., 2016. BMS-986165 Is a Highly Potent and Selective Allosteric Inhibitor of Tyk2, Blocks IL-12, IL-23 and Type I Interferon Signaling and Provides for Robust Efficacy in Preclinical Models of Systemic Lupus Erythematosus and Inflammatory Bowel Disease. ACR Meet. Abstr. Neubauer, H., Cumano, A., Muller, M., Wu, H., Huffstadt, U., Pfeffer, K., 1998. Jak2 Deficiency Defines an EssentialDevelopmental Checkpoint in DefinitiveHematopoiesis. Cell 93, 397-409. https: / / doi.org / 10.1016 / S0092-8674(00)81168-X O’Shea, J.J., Plenge, R., 2012. JAKs and STATs in Immunoregulation and Immune-Mediated Disease. Immunity 36, 542-550. https: / / doi.org / 10.1016 / j.immuni.2012.03.014 Parganas, E., Wang, D., Stravopodis, D., Topham, D.J., Marine, J.-C., Teglund, S., Vanin, E.F., Bodner, S., Colamonici, O.R., van Deursen, J.M., Grosveld, G., Ihle, J.N., 1998. Jak2 Is Essential for Signaling through a Variety of Cytokine Receptors. Cell 93, 385-395. https: / / doi.org / 10.1016 / S0092-8674(00)81167-8 Schwartz, D.M., Bonelli, M., Gadina, M., O’Shea, J.J., 2016. Type I / II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat.Rev.Rheumatol. 12, 25-36. https: / / doi.org / 10.1038 / nrrheum.2015.167 Sohn, S.J., Barrett, K., Abbema, A.V., Chang, C., Kohli, P.B., Kanda, H., Smith, J., Lai, Y., Zhou, A., Zhang, B., Yang, W., Williams, K., Macleod, C., Hurley, C.A., Kulagowski, J.J., Lewin-Koh, N., Dengler, H.S., Johnson, A.R., Ghilardi, N., Zak, M., Liang, J., Blair, W.S., Magnuson, S., Wu, L.C., 2013. A Restricted Role for TYK2 Catalytic Activity in Human Cytokine Responses Revealed by Novel TYK2-Selective Inhibitors.J.Immunol. 191, 2205-2216. https: / / doi.org / 10.4049 / jimmunol.1202859 Vainchenker, W., Dusa, A., Constantinescu, S.N., 2008. JAKs in pathology: Role of Janus kinases in hematopoietic malignancies and immunodeficiencies. Semin. Cell Dev. Biol.19, 385-393. https: / / doi.org / 10.1016 / j.semcdb.2008.07.002

Claims

1. A compound according to formula I, 【Chemistry 1】 During the ceremony, X １ and X ２ are independently N or CH; X ３ is NR ３ , O, or CR ４ａ R ４ｂ and R １ is H or -CH ３ and R ２ is H or -CH ３ and R ３ is H or C unsubstituted or substituted with one or more halo １－２ is alkyl, R ４ａ and R ４ｂ are independently H, —CN, —N(CH ３ ) ２ , or -CH ２ -OH, or a pharmaceutically acceptable salt / co-crystal thereof, or a solvate or a solvate of the salt / co-crystal thereof.

2. X １ The compound of claim 1, wherein is N, or a pharmaceutically acceptable salt thereof.

3. X ２ The compound of claim 1, wherein is N, or a pharmaceutically acceptable salt thereof.

4. X ３ But NR ３ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:

5. R ３ is H, -CH ３ , or -CH ２ CF ３ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

6. X ３ But, CR ４ａ R ４ｂ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:

7. R ４ａ is H and R ４ｂ The compound according to any one of claims 1 to 3 and 6, or a pharmaceutically acceptable salt thereof, wherein is -CN.

8. X ３ The compound according to any one of claims 1 to 3, wherein is O, or a pharmaceutically acceptable salt thereof.

9. R ２ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein is H.

10. R １ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein is H.

11. The compound according to claim 1, or a salt / co-crystal, or solvate thereof, or a solvate of the salt / co-crystal thereof, wherein the compound is 5-((7-((6-(2,3-dihydro-4H-1,4-oxazin-4-yl)pyridazin-3-yl)amino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)-4-methylpicolinonitrile (Compound 1). 【Chemistry 2】

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to any one of claims 1 to 11.

13. 12. The pharmaceutical composition of claim 11, comprising an additional therapeutic agent.

14. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12 or 13, for use in medicine.

15. 14. The compound according to any one of claims 1 to 11, or a salt / co-crystal, or solvate or a solvate of the salt / co-crystal thereof, or the pharmaceutical composition according to claim 12 or 13, for use in the treatment or prevention of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving disorders of cartilage metabolism, congenital cartilage malformations, and / or diseases associated with hypersecretion of IFNα, interferons ("interferonopathies", in particular type I or type III interferonopathies), IL-12, and / or IL-23, in particular a disease selected from systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease.

16. 14. Use of a compound, or a salt / co-crystal, or solvate or a solvate of the salt / co-crystal thereof, according to any one of claims 1 to 11, or a pharmaceutical composition according to claim 12 or 13, in the manufacture of a medicament for the treatment of inflammatory diseases, diseases associated with hypersecretion of IFNα and / or interferons ("interferonopathies", in particular type I interferonopathies), IL-12 and / or IL-23, in particular a disease selected from systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and / or Crohn's disease.

17. 14. A method for treating inflammatory diseases, diseases associated with hypersecretion of IFNα and / or interferons ("interferonopathies", in particular type I interferonopathies), IL-12 and / or IL-23, in particular a disease selected from systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjogren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and / or Crohn's disease, comprising administering to a patient a compound, or a salt / co-crystal, or solvate or a solvate of the salt / co-crystal thereof according to any one of claims 1 to 11, or a pharmaceutical composition according to claim 12 or 13.

18. 18. The compound for use according to claim 15, the use of the compound according to claim 16, or the method according to claim 17, wherein the disease to be treated is systemic lupus erythematosus, dermatomyositis, polymyositis, psoriasis, ulcerative colitis, and / or Crohn's disease.

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